SA04250311A - Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof - Google Patents

Abstract

The present invention relates to compounds of Formula I or pharmaceutically acceptable salts thereof wherein R1, R2, R3 and Ar as defined in the full description in addition to pharmaceutical salts and compositions comprising these compounds. It is useful in treatment, especially in the treatment of pain.

Description

. Ed' (Penbs derivatives (J gis) and compounds containing Wd pas and their use) Full Description BACKGROUND The present invention relates to therapeutic compounds and pharmaceutical compositions containing such compounds. and processes for their manufacture and uses. In particular; The present invention relates to compounds that can be effective 2 212 tT (tf), cancer, multiple sclerosis, Bar-Kinson's disease, chorea, Huntington's disease, Alzheimer's disease, BL-related disorders, intestinal tract disorders and/or cardiovascular disorders. GENERAL DESCRIPTION OF THE INVENTION Many years ago, LY therapy became one of the all SVs to which the study was directed.It is well known that the binding groups of a ci-like receptor (such as CB receptors, 0 receptors and 68 receptors) in yama These auxiliaries, antagonists, and antagonists induce pain relief in many animal models by interaction with CB and/or q0 receptors. ,© Primarily in the periphery By LL is restricted to cells and tissues derived from the immune system. Although 68 receptor agonists such as =A% tetrahydrate, cannabinol (1117-47) and anandamide Vo are useful in antinociceptive models in animals, WB tends to cause side effects.

undesirable effects on the central nervous system; Such as psychological side effects, potential for use cg bl, dependence on medication, tolerance, etc. These unwanted side effects are known to occur via 08 receptors located in the central nervous system. However, there is evidence to suggest that adjuvants that act at peripheral sites or have limited metabolism of the central nervous system can treat pain in humans and animals with an improved holistic treatment scheme in vivo. Therefore, there is a need for new OB-08 receptor ligands such as adjuvants that could be useful in managing pain or treating other related symptoms or diseases with minimal or minimal undesirable side effects on the central nervous system. 0 \ lowest. Detailed Description The present invention Sle got provides a ligand for a ,08 receptor that may be useful in the treatment of pain and/or other related symptoms or diseases. ¢ Ov is specified [8 Full Description] The designations used in this \o full description generally follow the examples and rules set forth in the Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is used here as a reference regarding sel chemical formulas and the rules used in naming chemical formulas. CB receptors are aware; [CB; CB receptors; arr.CB;

. The expression "or" or "with an Mb group" when used alone or as a padna means Ls ae gash from m to 11 carbon atoms. The expression "hydr and carbon" when used alone or as a suffix or (asl) denotes any structure that includes only carbon and hydrogen atoms (VE emg) a carbon atom.

0 The expression "hydro-carbon radical" or "hydro-carbyl" when used alone or as a compound or as a precursor means any ay resulting from the removal of one or more hydrogen atoms from the hydrocarbon. : guy is the term "alkyl" when used alone or as a suffix Woh or a monovalent straight-chain monovalent carbon hydroxide or ashi moiety containing between 1 and 11 carbon atoms. Unless otherwise stated »; the term “LSU” generally includes both saturated alkyl oH and non-0 hydrocarbon double radicals aly and means the term "alkylene" when used alone or as a suffix or as a carbon atom; 17 or 1 The symbiosis is of a straight or branched chain that includes between

It serves to connect two structures together.

The expression “alkenyl” when used Jaf, 03 or as a suffix or prefix” refers to a straight or branched chain monovalent 10 hydrocarbon moiety with one carbon bond = one double carbon

At least it includes what ranges from? And 1 carbon atom.

The expression "alkenyl" when used as a suffix or prefix af, 03 refers to a straight or branched chain monovalent hydrocarbon moiety having at least one carbon-carbon triple bond and comprising between ? And 71 carbon atoms. The expression “alkylcyclo” when used “aL, 03” or as a suffix or prefix” refers to a ring-containing monovalent hydrocarbon-0 moiety comprising between ? And 71 carbon atoms. The JS expression "cyclic" includes both the monocyclic and polycyclic hydric and carbon forms. Polycyclic hydride and polycyclic forms include beneficiary rings, non-beneficent rings, and bridged rings. “JSUT cyclic” when used alone or as a suffix or asl denotes a 0 hydrocarbon moiety, a ring-containing monovalent carbon-carbon double bond containing between ? and 1 carbon atom. The term “cycloalkenyl” includes “both single and polycyclic hydrocarbon forms. Cold and polycarbonate forms include non-branched rings; “branched rings” and “gang-connected” rings. as a suffix or prefix” to a monovalent carbon hydroxide moiety that contains a ring and has a carbon = carbon triple bond and contains between 1 and 1 carbon atoms. The expression “aryl” when used alone or as a suffix or prefix refers to the hydroxide and carbon in it One or more carbon rings have many unsaturation positions and are characterized by the aromatic ody view

: B

08 + unlocalized electrons (Y) and have between * and 41 carbon atoms, where the slit is on a carbon atom in the aromatic ring.

The term de pest “non-aromatic” or “non-aromatic” when used alone or as a suffix or ail denotes a derivative or a chemical group that does not contain an aromatic ring (i.e. non-electrons).

0 is positioned 0t + ?).

The expression “arylene” when used alone or as a suffix or genitive” refers to a divalent hydrocarbon moiety having one or ST of carbon rings for which Us has many nonradioactive positions iy of an aromatic property (i.e. having unlocalized electrons (n + ?) which have between 0 and 41 carbon atoms” and serve to hold two structures together.

uy 0 the term “heterocyclic compound” when used alone or as a suffix or prefix” for a structure or molecule containing a single Us ring or ST of polyvalent heteroatoms that are each selected separately from 18 and 0 and « and 8 as part of the loop structure and contain between ? and 1? An atom in the ring (or rings) (say) The cyclic compound is inl unsaturated or unsaturated and may contain one or more double bonds;

Ve is that the heterocyclic compound contains more than one ring. When the homocyclic compound contains an ST of 'Jaa', the rings can be denatured or non-dendritic. In general, declension rings refer to at least two rings sharing two atoms between them. A heterocyclic may or may not have aromatic properties.

2 no The term LS heteroatom “when used alone or as a suffix or prefix” refers to a moiety formed as a result of one or more hetero-atoms chosen from among 17, 0, “, and 5 being substituted for one or more atoms in the alkyl group. omy the term “heteroaromatic” when used alone or as a suffix or prefix” a ring-containing structure or molecule having one or more polyvalent hetero-atoms each selected separately from the SHPO IN as part of the ring structure; comprising Between 7 and 1 7 atoms in the ring(s) where the ring-containing or ring-loving fs A structure has an aromatic nature (i.e. it has 08 + unlocalized electrons (Y) and the term “group” denotes from a heterocyclic compound” or “a part of a heterocyclic compound” or “heterocyclic” when used alone or as a suffix or prefix” to a moiety derived from a heterocyclic compound by removing one or more hydrogen atoms from it. “with a heterocyclic group” when used con jak or as a suffix or prefix: » to a moiety of a heterocyclic compound by removing at least one hydrogen atom from the carbon in one of the rings Cyclic compound. VO and the term “heterocyclic PSI SW group” when used alone” or as a suffix; lf to a moiety of a heterocyclic compound obtained by removing (3,3) hydrogens from it and then serving to bind two structures together.

. - The term “heteroaryl aryl” when used alone or as a suffix or asl denotes a heterocyclic compound with aromatic properties” where the heterocyclic moiety AH is located on a carbon atom of the aromatic ring of the heterocyclic compound” Say The heteroaryl aryl contains both aromatic and non-aromatic rings, and these rings may be fused or joined together. The expression “heterocyclic alkyl” when used alone or as a suffix or cass denotes “and heteroarylene” when used alone or as a suffix or prefix”; to a heterocyclic group with aromatic properties. 1 The expression 'heterocyclic alkylene' when used as a suffix af, 03 or J SE TY denotes a divalent cyclic group that is not aromatic in nature. 'with six atoms' when used as a prefix indicates » dese is a six-atom ring The expression “with five atoms” when used as a prefix refers to a group with a ring containing five Yo atoms A five-atom heteroaryl ring is a heteroaryl with a five-atom ring where the Atoms number 1, ?or ?, each separately, from 37, 0, and 8.

_ 9 -— x, Examples of heterogeneous aryl groups with five atoms can be mentioned thienyl, furyl, ay, pyrrolyl, imidazolyl, thiazolyl, ala, xazolyl, pyrazolyl, and isonmazolyl (Jd thiade = F 7 Oy Walterazolyl” (JT, Elise, Xazolyl” and “1” 7 #3-Tri-thiadiazolyl; - 4 or 1 and tri-azolyl.

A heteroaryl with six atoms is a heteroaryl with 16 atoms in the ring where

choose 1 or ? Or 7 of the atoms of the ring - independently - from 17 », 0 and 8. An example of a heterocyclic aryl with six atoms is puridyl

0, pyrazinyl, birbamidinyl, triazinyl, and pyridazinil. When using the expression a “substitute” it means a formula or or or a group in which IM} Ole gost has one or more hydrocarbons 2 or more J= one hydrogen atom or ach or with one or more chemical groups containing on one or more heterogeneity atoms to be chosen from 07, 5, 7, 1©, 3: [1 and . Examples of chemical Ole gusts containing one or more SE Vo atoms include Le:

NOz, -OR, -Cl, -Br, -I, -F, -CF3, - C(=O)R, -C(=O)OH, -NHz, -SH, -NHR, -NRz, - SR, - SOsH, -SO2R, -S(=O)R, - CN, -OH, -C(=0)OR, -C(=0)NRz, -NRC(=O)R, » oxo (= 0), imino (RNS), niu-8)” and ximino (RON) where each “8” is a Cr hydrocarbyl. For example, an aryl substituting 0 may be referred to as nitrophenyl, piperidylphenyl, methoxyphenyl, chlorophenyl, or amino

11 “phenyl” etc. where nitro, pyridyl, “eS lly, chloro” and amino groups can replace any suitable hydrogen in the phenyl ring. When the term "substituted" is used with respect to a structure, molecule, or group and is followed by the names of one or more chemical groups, it refers to a second structure, molecule, or group resulting from the replacement of one hydrogen atom or 0 by one or more chemical groups (sland) Amore than the first structure, molecule, or group. For JU, "nitro-substituted vinyl" stands for "nitro-vinyl". The term "optionally substitutable" refers to each of the groups, combinations, or molecules that may or may not be substituted.

0 The heterocyclic CST includes - for example - cyclic compounds with one ring such as: aziridine, xerane, thiarene, azitidine, a-oxetane, theetane, cop apr, pyrroline, imidazolidine, pyrazolidine, pyrazolin, di OXOLAN “Sulfolane 7 = F dihydrofuran” 7 0— dihydrofuran “tetrahydrofuran” OB bipyridine CF 7 0 -1 tetrahydropyridine; Piperazine » Morpholine » Teomorpholine » Piran » Tuberana CY ?-Day

“YF dioxane den 1-4-dihydropyridine” 1-4-dihydropyrane “tetrahydropyrane” 0 esl -111- tetrahydro-17 4 7 7 di or di-xane or homopyridine-xane "di oxpain; and hexa-7"0-dihydro =V cf dioxypan" 7-1 methylene homoperazine or oxide. In addition, the expression of the heterocyclic compound includes noncyclic aromatic compounds

0 congeners such as pyridine, pyrazine, pyrimidine, pyridazine, and thiophene; furazin;

-11-: furans, pyrols, imidazoles, thiazoles, or oxazoles; pyrazole, isothiazole, alise, coxazole = v or ay triazole, tetrazole and 1 oY = Y diazole RA -Y oxa diazole (HANAN) - triindole (hols -4 Yo) Azole AAR; In addition to (5) heterocyclic expression of CSA includes heterocyclic compounds such as indole, indole, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxane; coumarin; hydr, cumarine, “jolly furan,” 7 “= dihydro-ptzfuran,” and isobuterfuran; purine, phinephalazine, naphthalpyridine, alkene, xazole, quinazoline, cinolin, teridine, phenanthridine, percidine, phenanthroline, phenazine, phenothiazine, phen, xazine, 1?-benepase and xazole; benzothiophene, benzoxazole, benzthiazole, and benzimidazole Benztiay (0 Jail), thio-xanthin, carbazole, carbolene, acridine, pyrrolizidine, and quinolizidine. In addition to the previously explained polycyclic heterocyclic compounds, the heterocyclic compound includes polycyclic heterocyclic compounds in which the end Annular MAG between two rings or ST has more than one bond common to both rings. Examples of such heterocyclic compounds include the alkene and clidin bridges, di-aza by 00 cyclo 0 1 Ola and/a-oxa by cyclo Ole [Voy oY]

-17- “Jody” heterocyclic compounds, for example, monocyclic heterocyclic compounds such as aziridinyl, pyralidinyl, piperazolinil, dia and oxolanil; Oxiranil A, Pyralidinil, Piperazolinil, DAI Xanolanyl Nai Iranyl; azetidine; A, thietaniyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyralidinyl, piperazolinyl, 0, dioxolinyl, and sulfolanil, 7=F dihydrofuranyl; 7,-0-dihydrofuranyl, tetrahydrofuranyl, thiofanyl, piperidinyl, SA NCA 0, 7-tetrahydropyridinyl, piperazinyl, morpholine, thiomorpholinyl, puranyl, liopyranyl, 7?-dihydropyranyl, tetrahydropyranyl, 1, 4-di hydropyridinyl',1',4-di-oxanyl; ¥en dieaoxanyl, diaoxanyl, homopipredinyl, 1-4 TY tetrahydro = 0 151azienyl, and homoprazinyl, 1 3-diaoxanel, 4l1-dihydro-1 ?- Die Auxinelle» and 4; -1-dihydro FV dia-oxyenyl and hexamethylene a-oxidyl. In addition, heterocyclic expression of CSN includes heterocyclic or hetero-aryl aromatic compounds such as pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and thepenyl; furyl, furanazil, pyrrolil, and imidazole; thiazolyl” 0 oxazolyl” pyrazolyl” isothiazolyl” alaise and xazolyl” = F eX Ay triazolyl” tetrazolyl” 1 WT oY diazolyl” and 1” = v oY oxa diazolyl; 1 “4-triazolyl” and 1or 4-thiadiazolyl oY ag-oxa diazolyl Vy er 4-triazolyl and 1or 4-thiadiazolyl or In addition, the term heterocyclic CSU includes non-0 homocyclic polycyclic compounds (including aromatic and non-aromatic) such as indolyl and indolyl

are: isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydrois, quinolinyl, 1-4-benzodioxanyl, coumarinyl, dihydr, coumarinyl, andlfuranyl, 7,7-dihydroptzofuranyl, and iso Petro Fiorel and Chromenell; z-chromanyl», isochromyl», isochromyl, zathinyl», valine and rexainyl; 0, theanthrinyl, indolisinyl, isoindolyl, indazolyl, and pyurithyl; Walphthazine »

naphthridinyl, alkene, xalienil, quinazolinil, cinolinil, tridinil, and phenanthridinil; birbamidanill, phenyanethrolinyl, phenazinyl, phenothiazinyl, phenoxanzenil, 1,1-benzoisoxazolyl; benzo-theophenyl, benzo-dexazolyl (Jd asd edly), benz-amidazoleyl, benz-tri-azolelyl, thioxanthenylyl, carbazolyl, and carbonyl

0, acridinyl, pyrrolizidinyl, and quinolizidinyl. In addition to the aforementioned polycyclic heterocyclic compounds, the heterocyclic compound includes polycyclic heterocyclic compounds where the cyclic fusion between two or more rings includes more than one common bond in both rings and more than two common atoms in both rings. Examples of such heterocyclic compounds containing

0 Elkin and Clydinel Bridge,” Asa’s parents by Cyclo [VY or] Hethel; and/a- Oxabay Cycler [10 1 oY] Hepnel. The expression "alk and x" when used alone or as a suffix or cl means radicals of the general formula 0-18 -0 where -18 is chosen from a hydrocarbon radical. Examples of alkoxy include: methoxy, ichoxy, propoxy, isoprop, and C:; (eS Samy wa -

-16- .

butoxy, isobutoxy, cyclopropylmethoxy; and allyl eS 3h and propargyl-oxy. The expression "azyloxy" when used alone or as a suffix or prefix refers to moieties of the general formula Ar - 0 - where Ar is an aryl.

0 and the expression "heteroaryl oxy" when used alone or as a suffix or asl denotes moieties of the general form of 0 - where Ar - is a heteroaryl. The term "eal" or "amino" when used as jaf, 03 or as a suffix or prefix denotes radicals of the general formula NRR' = ¢ where RJR is selected separately from a hydrogen or a hydrocarbon radical.

R where - C(=0)-R denotes the expression "acyl" when used alone or as a suffix or prefix; to 0 is an optionally substituted hydrocarbyl, hydrogen, amino or alkoxy . It includes - Acetyl ′′ Jed Carbo-acetyl; Propionyl » benzoyl - Jul acyl - for example Ole gest and dimethyl carbamoyl. o S ish and fluorine, chlorine, bromine and iodine. Sli SU includes

\o The term "halogenated" when used as a prefix for a water group indicates that one or more hydrogen atoms have been replaced by one or more halogen atoms. "RT" or nt! is defined as room temperature.

0 and 1 WB om that a first ring group is "subscribed" with a ring group LU that the first and second ring share at least two atoms between them. The expressions “link”, “connected” or “connection” mean unless otherwise indicated. bond or covalent bond. 0 and when iS gost or a structure or atom Jl is "directly attached" to a second group, structure or atom ols at least one atom of the first group, structure or atom forms a chemical bond with at least one atom of the group or structure or second atom. The term “saturated” carbon atom refers to a carbon atom in a structure, molecule or group where all the dal bonds to that carbon atom are single bonds. In the expression ge there are no 10 double or triple bonds attached to this carbon atom The carbon atom mentioned in general is subject to

to an atomic orbital denaturation SP?

The term "unsaturated carbon atom" refers to a carbon atom in a structure, molecule, or group where

At least one of the bonds attached to this carbon atom is a single bond.

In other words, there is at least one double or triple bond attached to the carbon atom oda 0 and the male carbon atom is generally subjected to an atomic orbital denaturation of the type SP or SP?

¢ The embodiment of the invention trims a compound of Formula 1 or a salt (lend one of the 3s

Or double FOES or a pharmaceutically acceptable isoform of it” or mixtures of the above.

ae : oF ) LN M 1 HAS R 3 i where: JER! from Wader (JS Rudy = Alkenyl Roy Sickler Alkyl Cray Alkyl Rami Cyclo Alkenel - “Cra Alkyl” Cay Cyclo Alkyl Heterogeneous = Ben Alkyl, 0310 Cyclo Alkyl “and Mim - Cyclo Alkenel” Cry Cyclo Alkyl Heterogeneous “as the ole post mentioned by Crag = Alkyl” Cay cycloalkenyl - alkyl mirth Cay scler JS heterocyclic alkyl Crug wood cyclo alkyl women = mikel alkyl rmen heterocyclic alkyl used in Rd with optionally substituted groups of one or more of the selected groups from com JU cyano, nitro, methoxy, uroxy, 0, ethyl, ethyl, hydroxy, and amino. Alkyl” and Meh Cyclo Alkenyl - Pm © - JS Whereas the mentioned groups of “JS Crag Woody = Alkenyl Rhono - Sickler (JS Rudi = Sicar Alkyl - Br - Alkyl used in distinguishing AR? with optionally substituted groups with one or ST No of the selected groups of halogens, methoroxy, ichoroxy, and methyl (JY Hydroxychloroquine and amino.

-\Vv- 0 Mos choose from Hydrogen” “JS = Cie and Mo - Alkenyl” and Min - Cycloalkyl ~Cs.69 Cycloalkyl — with - Alkyl. _css. 55S aryl - Cis heteroaryl where _Cs.69 is chosen from 60_aryl; f 0 = alkoxy; Cis alkyl amino carbonyl” and halogens. In another embodiment, the compounds of the present invention are those compounds that have the general i reall 1 where: © lj choose from (JJ = Cis, Min - Alkenyl, mmCycloalkyl — Cis = Alkyl. Cass CycloAlkenyl - bitter© (JST and heterogeneous cyclo-alkyl - bur-alkyl) where 1 0 the aforementioned groups are from (JS _ Cis and min alkenyl cis cyclic alkyl _ Cia _ = and min cyclokyl non contigant = b (JS Cia — the Cas (JS alkyl cyclases) used to characterize RE are optionally substituted for one or more SERV groups of halogen, methoxy, ishoxy, methyl, hydroxy, and amino. - Maine cyclo (JS cyclo Cie “JS Case” - Cis, choose from 2

Cie cited from Ole gas where “JS - Cia — Cycloalkenyl Cas? (JS - 4 \o Css ¢JuSH - Cas (JS = = cycloalkyl mucycline alkyl J - alkyl. Cass - cycloalkenyl — Cia - alkyl A used in R? jf are substituted groups Optionally with one or more of the selected groups of halogens, mishoxy, etoroxy, and hydroxy:

1- H a alkyl - Crag of hydrogen JER dil = choose from phenyl Wi = heteroaryl where the aforementioned heterocyclic Ar phenyl groups are groups optionally substituted by one or more of the groups fluoro, chloro, bromo, and iodo. oS My selected from methyl”] In another additional embodiment, the compounds of the present invention are compounds of the general formula ©: where: from cyclopentyl-methyl” and cyclohexyl-methyl “cyclobutyl-methyl JER - cyclopropyl-methyl” and 4,4-difluorocyclohexanemethyl” tetrahydropyranyl = methyl Nymethyl” tetrahydrofuranyl-methyl” morpholinyl-methyl” and piperidinyl ethyl” piperidinyl-methyl” and piperidinyl-methyl. DiVV gedaan meth, xy-7-propyl, 7-hydroxy-propyl, 1-methyl-11oyl, trifluoromethyl, 1-methyl-propyl, 11-dimethyl ?- trifluoroethyl butene” and ethyl” and ?- propyl-7 oY difluoroethyl “and 7” lee to choose from hydrogen and methyl “V” to choose from phenyl” and pyridyl” and percmidyl “and thiazolyl” and thinyl; Ease and xazolyl»Ar and epidazolyl»and pyrazolyl»as the aforementioned groups of pyridyl» and pyridyl

—_ \ q- The thiazolyls, thethenyls, the ezes, the xazolyls, the epidazolyls, and the pyrazolyls are groups optionally substituted with one or more of the selected groups of methyl, methoxy, fluoro, and chloro. The compounds of the present invention are those compounds having Lal And in an additional form where: (J) the general formula which is cyclhexyl-methyl “tetrahydropyranyl-methyl” and 4,4-difluoro-0 cyclohexanemethyl “b” is +- Butyl” and 111- difluoroethyl”R” choose from hydrogen and methyl § select from phenyl” and pyridyl” and thiazolyl and estyl and es and xazolyl” and imidazolyl. Any xazolyl, imidazolyl, and pyrazolyl groups are optionally substituted by one or more methyl and fluoro-methyl groups.

OL The invention on a single chiral center or OLS a It is understood that when it contains allomorphic or dual forms 3 - We patent compounds can exist - as well as OMS or doubles on any matcha JU stereoisomer or as a racemic mixture. The invention includes \o and it is possible to prepare pure images. I or mixtures thereof 4 for a compound of formula se a body or a chiral chromatographic racemate for the filly JE compounds optically of the compound of the invention »for example

. tubercle racemic; i.e., by synthesis from photoactive excipients or by non-synthesis based on the procedures to be explained. It will also be possible to understand that certain compounds of the present invention can exist in the form of engineering isomers »; as the BE and 2 isomers of alkenes. The present invention includes 0, any engineering isomer of a compound of formula 1. It is also understood that the present invention includes the ols of the compounds of formula 1. It is also understood that certain compounds of the present invention can exist in the form of solutes or hydrates” in addition to Pictures without hydrate. It is further understood that the present invention also includes all such solute forms of Formula 1 compounds.

0 The scope of the invention includes the salts of the compounds of formula 1. As with Wile, the pharmaceutically acceptable salts of the compounds of the present invention can be obtained using standard procedures known in this field, such as the reaction of a compound of sufficient basicity such as an alkylamine with a suitable acid such as 1101 or acetic acid” to obtain a physiologically acceptable anion. The corresponding alkali metal salt (such as sodium, potassium, or linium) or

0 the alkaline earth metal (such as calcium) by treating a compound of the invention JH having a suitable acid fraction such as a carboxylic acid; or a phenol with one equivalent of an alkali metal hydroxide or alkoxide or of an alkaline earth metal (such as ethoxide or mechoside) or an organic amine of suitable alkalinity (such as choline or meglumine) in aqueous media, followed by appropriate purification techniques.

-Y\-0

In one embodiment, the compound of Formula 1 can be converted to a pharmaceutically acceptable salt or solute, especially the salt of acid addition such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, and esters; Alishan sulfonate” or P = toluene sulfonate.

0 We have now discovered that the compounds of the invention have activity as pharmaceuticals; Especially as modifiers or ligands as auxiliaries, partial auxiliaries or inverse auxiliaries to ,08 receptors. And more specifically, the compounds of the invention “bles” appear as agonists for CB receptors, and they are useful in treatment; Especially for the relief of various pain conditions such as co MEY, neuralgia, acute pain, and pain caused by cancer; It is not caused by arthritis

0 rheumatoid arthritis” and migraine and visceral pain. However; This list should not be considered exclusive to Invention Glad. In addition, the compounds of the present invention are useful in other pathological conditions in which disturbance of 08,08 receptors is significant or significant. In addition to (els), the compounds of the invention can be used in the treatment of cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Fla disease, anxiety disorders, and ductal disorders.

0 Gastroenteritis and cardiovascular disorders. The compounds of the invention are useful as celia modifiers, especially 3 autoimmune diseases such as rheumatoid arthritis, cd vaccinations, organ transplantation and corresponding surgical needs, collagen diseases, and various types of allergies. And for use as antitumor and antiviral agents.

-7- 2

The compounds of the invention are useful in pathological conditions in which cannabinoid receptors are damaged or have a role in them. Such cases could include the use of radioisotope-labelled images of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission X-ray imaging.

0 and the compounds of the invention are useful in the treatment of diarrhea »; depression, anxiety, and stress-related disorders such as post-traumatic stress; eddy, generalized anxiety and social anxiety; Obsessive-compulsive disorder, lack of control of urine, premature ejaculation, various mental illnesses, coughing, pulmonary edema, functional disorders of the gastro-intestinal tract such as inflammatory bowel syndrome and indigestion, Parkinson's disease and other movement disorders, and injuries.

0 Disorders resulting from trauma, stroke, cardiac protection after myocardial infarction, injury to the spinal cord, drug addiction, including treatment of alcoholism, nicotine, opium, and other drugs, as well as disorders of the sympathetic nervous system such as high blood pressure. The compounds of the invention are useful as LOU-reducing substances used during general anesthesia and anesthetic care under observation. Wy combinations of materials with different properties are often used to obtain

AW balances the effects required to maintain the anaphylactic state (such as amnesia; 'No' and 'muscle relaxation' and analgesia). This combination includes inhaled narcotics, “anxiolytics,” neuromuscular blockers, and opioids. Also within the scope of this invention is the use of any of the compounds of the foregoing Formula 1; In the manufacture of a drug to treat any of the previously discussed conditions

- Sal -Y A further feature of the invention is to treat a patient Bl of any of the aforementioned conditions by administering an effective amount of the compound of the foregoing Formula 1. Thus the invention presents a compound of Formula 1 or a pharmaceutically acceptable salt or solute thereof; As previously defined for its use in treatment. 0 and os a The invention SUH provides for the use of a compound of formula 1 or a pharmaceutically acceptable salt or solute (a) as previously defined and that 3 manufacture a drug using 3 treatment. In the context of the full description (JU) the expression “treatment also includes “prevention” unless there are specific statements to the contrary. Thus, the terms “therapeutic” and “therapeutic” must be understood on the same basis. Also, the term “treatment” in the context of the present invention implies the administration of an effective amount of 0 of one The compounds of the present invention “to relieve a pre-existing disease condition” or an acute, chronic or recurrent condition This definition also includes preventive treatments for recurring seizures and for the continuous treatment of ASL disorders and the compounds of the present invention are useful in treatment “especially in the treatment of various pain conditions Including - but not limited to 'Y=1 acute 'Vy 1 compelling' and neuralgia; 'lal vo' pains 'pain due to cancer' and visceral pain. The compound of the invention can be administered in the form of a traditional pharmaceutical composition in any way, including orally, intramuscularly and under

AH, locally, in the nose, and in the peritoneum; in the breast and in the vein; Divide the dura mater and the inner sheath of the 3rd ventricle of the brain and inject into the joints. In one embodiment of the invention, administration can be done orally, intravenously, or intramuscularly. The dose will depend on the method of administration, the unit of the infant, the age and weight of the patient, and other factors that are taken into account by the attending physician, when determining the appropriate regimen and dose level for each patient. For the preparation of pharmaceutical compositions from the compounds of this invention, the inert carriers that are pharmaceutically acceptable can be liquid or solid. Solid formulations include powders; discs; dispersible granules, capsules, rivets, and suppositories. 0 The solid carrier may be one or more substances and cannot act as diluents or flavorings; or solvents, or lubricants, or admixture aids, or binders, or disintegrating materials, and may also be a material for use in capsules. For powders, the carrier is a well-powdered substance, where it is mixed with one of the compounds The invention is finely milled or with a granulator (JE) and in tablets (Yo) the component (JR) is mixed with a carrier with the required binding properties in acceptable proportions and les and to prepare the compositions in the form of suppositories; Vol is melted with a melting point As low as a mixture of fatty acid glycerides with cocoa butter, then the active ingredient is dispersed by stirring.

-Yo- 2 and allow it to cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium 0 carboxmethylcellulose, and melting point wax. The expression “combination” also includes the mixture of the JRA macaron with the encapsulating material in the form of a carrier providing a capsule within which the active macaron is surrounded by an associated carrier (with or without other carriers). This term includes the rivet. Suitable for non-gastrointestinal administration.WLS formulations may also be formulated in a polyVo solution of ethylene glycol.Sy Prepare aqueous solutions for oral administration by dissolving the Jill ingredient in water and adding Mo Add Wika suitable flavorings, stabilizers and thickeners as desired. Aqueous suspensions for oral administration may be made by finely ground dispersions of the JE ingredient 3 = Water

I - “-Y 0 viscous substance, such as natural and synthetic glues” and resins; Jilly cellulose, sodium carbonate, oxymethyl cellulose, and other suspended materials known in the case of pharmaceutical formulations. According to the method of administration, “it is preferable that the pharmaceutical composition include between 960.06 and 9095 by weight (percentage by weight)” and it is preferable that it contain between 1.1 and 0 2050 by weight of the compound of the invention. . It is possible to determine the effective amount for the implementation of the present invention, using the criteria GL ay al that age, weight, and the response of each patient individually; It is determined in the light of the disease that is being treated or treated, by someone who has normal skill in this field. It is within the scope of the invention to use any compound of Formula 1 as previously defined for the manufacture of a drug. 0 Also within the scope of the invention is the use of any compound of formula 1 in the manufacture of a drug for the treatment of EV. J also falls within the scope of the invention the use of any compound of formula 1 in the manufacture of a drug for the treatment of [REE HEPA] conditions such as - for example Examples are not limited to acute pain, chronic pain, neuropathic pain, back pain, cancer-related pain, and visceral pain. Another feature of the invention is a method for treating a patient LA of a condition of V0 previously discussed by administering an effective amount of the compound Uy of the foregoing 1 formulation. In addition; A pharmaceutical composition shall be provided that includes a compound of the formula [» or a pharmaceutically acceptable salt thereof. In combination with a pharmaceutically acceptable carrier.

-YV- - In particular, a pharmaceutical composition comprising a compound of formula ] or a pharmaceutically acceptable salt (de) in combination with a pharmaceutically acceptable carrier HE oz Ml of dg dl is provided for the treatment of pain. » A pharmaceutical composition comprising a compound of formula J or a pharmaceutically acceptable 0 salt terminated in combination with a pharmaceutically acceptable carrier is provided for use in any of the cases previously discussed. In another the invention is a method for preparing the compounds of the present invention. embodiments; the method of the invention is a method for preparing the compound of formula [ae 3 other] The invention SUH provides a method for preparing the compounds of this invention. Tela ATS CL 2 © R' I The process involves the reaction of a compound of general formula [1 x a or l 1 mosem N © R 1 I ‏

: Sl with the compound of formula 82007 in the presence of a base material such as an alkylamine” and optionally in the presence of a coupling material such as (HATU and 2000 where: X - selected from Bry 71 and 7 COH) B: “JER - From Mn© Alkyl and Mede = Alkenyl Coy Cyclo Alkyl (SI Cray Cas y ° Cyclo Alkenyl = Crs Alkyl Cay Cyclo JST Heterogeneous = Crs Alkyl Wamadek Cycloalkyl “Cay - Cycloalkenyl” Cry Cycloalkyl heterocyclic “Em The male groups of (SIT = Crago and Mine Cycloalkenyl - M Alkyl” Cay Cycloalkyl heterocyclic “JS Crp” Woody cyclic (JS Cas - cycloalkenyl Cog cyclo SU the heterocyclic used in Ease 1 is an optionally substituted group for one or more select groups of halogens; cyano, nitro and methoxy; and ethos as a bad and for methyl” (dy) and hydroxy; and amino. JER? = from wadr = alkyl rudi-alkenyl Roon - cyclo-alkyl; ru-cyclo-alkenyl - Crp - alkyl” and cyclo-alkenyl - Cry - alkyl” wherein Vo mentioned groups of Cragg Alkyl Caan g = Alkenyl Caro g = Cyclo (JST Cao - Cycloalkyl - M t = the alkyl used to distinguish 18 Gs optionally substituted by one or ST from the selected groups of oligomers and methoroxy; ichoxy, methyl, and ethyl; hydroxychloroquine; and amino.

0 - and 7- 0 - C choose from hydrogen” and M© = alkyl” and from = alkenyl” Cry = cyclo (JST —Cs.6.9 cyclo alkyl — Cig = alkyl. Ar - choose from Coo = aryl » Cay = hetero-aryl » where said Cig - aryl and said mo - aryl hetero-aryl are groups optionally substituted by one or AST Qo from le past chosen from Cis - Alkyl, Cis-alkoxy, Cis, alkyl amino carbonyl” and halogens. The compounds of the present invention can also be prepared according to the synthetic pathways shown in Scheme Fo.

a 0 because 1 kh 1 is a base, 2.5. NaH } Do sciverd, eg.

DIF Uncle HM ME, TX i 5 6 : 2 IK ——_— base ap DMAP a Tr -— aj sofesnt, e.g.

CH,Cly F 2: RSH, teg e.g. .5852 : had = EHH and let solvent, mume = *msum Hy, Pd 5 oh reduction, 14 = vs R . 1 RC, sees, 02 OO oo ik 2 - 2 sim LED - o N Ag NH 2 C0 f QD 01 14 Hay Bran R AT 1 SHARP ga in 8 0 bass, eg.

THE curlers se 4 pr be skipped 1 d when they bite base, ag. sateen, e.g.

DMF coupling reagent, 2.7 HATY AcOH and BAD;2 Bd, e.g.

Aon BIG ICrOWaVE ver hadting, As, Bt, Rand R3 are 3s delned in the spacifications. a and Cr 2 Vel Ne 1 0 RAH “YO —_- c ttt ttt base, 2.9. TIPEA 3 3 base, e.g.

EIN < MH £ schmnt, 8.3. SHCL savers.

Bg.

A mag Li, and e e.g.

H,, Pd Po 13 vecuting pent, Hah ‎solvent, e.g.

TAS 0 = oe THF Wo 2 wurg Hh Ee = Lae 3 sichvent, 3 e “baker a — blacks 5 3 a Coy 2 27501 Cy 2:0 eg l when = i a! a WEG 8.8 a DMAP and a base, solvent, 2g.

THT, nag whan: base, ag FEA DHF a a solvent, HAT and k supiing reagent. Act and Fp soivant, acid, e.g.

AcOH microwave owen heating, 10% 180PC ang RZ are as defined in the specifications.

-ry- 0“ Scheme 0 9 A . RH G i?

HO, 2 mir 2 8 sim HO,

F ) base, 2.3. EL N o ns soheant, =. Eg

EtOH 7 14 resfsziion, 2.g. Hy, Pd 5 po] scheent, e.g. E2380 a 8 9 i

Ls i 0s TE Bht 23 RACE 2 8 tower a vi piers WCE wr basa, d NaH base, e.g. DVRS scleent, e.g. DF sobsent, e.g. CH; : wan c baze, wt FEA sabvent, eg. DMF: 55112419 reagent, e.g. HATU. 3: Madhah 2.3. AoCH avid, e.g. ASCH microwave Oven healing, 100-107

Ar. RY, QB and RS are as defined in the specifications. 1 0 RETR and a0 1} hase, e.g. Mak ar

FIR the sowed, and the an i ] Kat Afik Mio “{| We 2528 ey © Tia La:

R &

Ws Cor Z's 5 base, eg Mak solves, e.g. THF 2244 3 N= 7 and o i

As EM 5 1 & . fant “3 5 [3 fi.a

Ria © Lawal Re, RY, amd Ar are Kana'a varieties in the specifications. Biological evaluation: hCB, 3 hCB; bind the receptors

-Yy- 2 0 A human receptor© from (Receptor Biology) Jol) 603 or a human CBy receptor from (hCB,) (Biosignal) membranes are dephosphorylated at a temperature of dust YY and pass it? times through a blunt-needle-Yo tolerance meter and diluted in a cannabinoid-binding buffer (00 mM Tris, 0.5 mM Tris, ¥ 0.0 mM EDTA, ¥ 1480 105+ Baham/0 mL 858 stearic acid-free; pH 1,4) Equal parts that contain an appropriate amount of protein are distributed on dishes with a capacity of AT in kind. The L and 10 of the compounds of the invention are evaluated at ,1105 and 103 with dose-response curves of -01 points made using 940 311-0055 at 1 to JE Yee per minute per eye (ALYY - AY molar) in the body of JU. 3000 microliters. Total and nonspecific binding are determined in 0 presence and absence of 1.7 μm of 171 210, respectively. vigorously stir and place dishes in wad) for 60 minutes at room temperature; and filtered through 67/8 mono filters (Laie soaked in 960,1 polyethylene imine) with Tomtec collector or 0 using ? ml of buffer wash solution (0 5 mM Tris and 0 5 mM MgCl, + BSA pH 7). The filters are agitated for 1 hour at 0 °C. The sual radioactivity (sual per minute) is calculated in a Top Count (Packard) counter after addition of 10 µl/eye of scintillation fluid 20 MS-binding GTPyS; hCBsy hCB; human CB receptor (hCBy) from (Receptor Biology) or 3280 human receptor D63 from (Biosignal) is thawed at a cryopreserved YY temperature and passed? times through a blunt needle-Yo tolerance meter and diluted in 61078 L's binder buffer (50 mM

0 No Hepes, 1 mM NaOH, 1100 mM NaCl, 1 mM EDTA, and 5 mM MgCl « pH og (BSA 201.13 V, t) Emax rating y ECso of the compounds of the invention with 01-point dose-response curves made in 00 μl with an appropriate amount of membrane protein Vong = 00000 decomposition per minute for 0 070:55 in each eye (VY -1.14 nanomolar) . Maximum base activated binding is challenged in the absence or presence of 1 μM (WCB) or 01 μM -55.212 (hCB1) Win 2 respectively and the membranes are pre-incubated for ©07 min. Y0 μm (hCBy) or 0, My μmolar GDP 108 before distribution to V0 dishes) μm (HCBy) or 701 μm (JU 003: GDP) Vigorously stirred, incubated for 0 min at room temperature and filtered on GF/B monofilters (pre-soaked in water) with Tomtec or Packard collection media using ¥ ml washing-up solution Regulator (00 mM Tris, mM H, [3480 and 1 5 mM NaCl] pH (VY) and filters are added for an hour at a temperature of 5 °C. Radioactivity is calculated (in kits per minute) in TOP Count (Packard) after addition of 16 μl Vo/eye of flash fluid 20-348. Reverse antibody studies are performed in the same way” except that: (a) an adjuvant dose response curve is made in the presence of a concentration is a constant for the antigen or (b) go is made in response to the dose of the antigen in Having a fixed focus of the assistant. And based on the previous tests, the decomposition constant (Ki) is determined for a specific compound of the invention ol 0 a specific receptor using the following equation: ,(160/[H:]+10:0/)1 = Ki

MM and where ICs is the concentration of the compound of the invention at which an offset of 0 70.5 A [rad] is observed to be a standard or reference do gat ligand radioactive concentration at that moment; And Kd is the decay constant of the radioactive ligand group towards a particular receptor. © Wim Using the aforementioned tests, measurement of the nictitation of CB receptors, human, for most compounds of the invention so that it is in the range from 0,000 to 0,000 nanomolar. The Ki measured by human CB receptors for most of the compounds of the invention is in the range of about 0.8 to 77.7 nM. The old ECso (human CB receptors) for most of the compounds of the invention are measured to have a value range of about 7 veo Ji bd y/namolar. For most of the compounds of the invention, a) L_ 1 7 Bah CB receivers are measured so that it is 3 range from about A to OVR. Examples This invention will be described in more detail through the following examples that describe the methods that can be By which the compounds of the invention (JU) are prepared, purified, analyzed, and tested biologically (1), and these are methods that do not like to be interpreted as being restricted or specific to this invention. Example: 1 N - [?- p - butyl -1 - (cyclohexylmethyl)ju —HY=imidazole —0— yl]thiophene-?-sulfonamide:

. and NI ToC MN: 0

Step A: 18-[3- + -butyl-1-(cyclohexylmethyl) = ju HY imidazole -

8-yl]thiophene—Y—sulfonamide:

a 5 eas 1 a N l of 0 0 dissolved 38 - ov}amino-4-[(cyclohexylmethyl)amino]phenyl)thiophene-?-sulfonamide (00) al (100 mmol) (For the method of preparation, see steps b) c) d (Gal) in ¾ ml of 1,1-dichloroethane containing TEA (dt TO) 08 mmol). Drops of trimethyl acetyl chloride (0 07 ml; 59 + mmol) were added and the solution was stirred at room temperature for 1 hour. Also, 0 (1 ACOH ml) was added with a few drops of concentrated hydrochloric acid, and the solution was stirred under 80 °C overnight. Then the solvent was evaporated and the crude product was dissolved in EtOAc, then washed with an aqueous solution of sodium hydroxide (ZM) and pyrene and dried with anhydrous magnesium sulfate. The product was further purified by reverse-phase HPLC with Yo JOA + - from a mixture of 01307 (H,0) and then lyophilized to yield the title compound Vo as the corresponding M17 salt.

+ 1 m H NMR (400 MHz, METHANOLD4): 1.19 § (m, 5H), 1.57 (m, 110, 1.59 (m, 1 H), ~~ 1.61 (s, 9H), 1.66 (m , 1 H), 1.73 (m, 2 H), 2.05 (m, 1 H), 437 (d, J=7.62 Hz, 2 2 (dd, J=4.98, 3.81 Hz, 1 H), 7.25 (dd, J=8.98, 2.15 Hz, 1 H), 7.52 (dd, J=3.71, 1.37 Hz, 1

H), 7.66 (d, J=2.15 Hz, 1H), 7.69 (dd, J=5.08, 1.37 Hz, 1H), 7.76 (d, J=8.98 Hz, 1H);

MS (ESI) (M+H)+432.1; Anal. Calcd for C22H29N30282 + 1.4 TFA + 0.6 H20: C, 49.48; ©

H, 5.29; N, 6.98. Found: C, 49.47; H, 5.36; N, 6.83. Step N10 - (4-fluoro-0-tetrophenyl) thiophene —¥— sulfonamide 0 spray HM NO, “Behala — TL . 4-Fluoro-7-nitroaniline 1 (g 6.51 mmol) was stirred; And 3-thiophenesulfonyl chloride (V, V0) chloride” 9.77 mmol) in an amount of dichloromethane of 101 ml and stored on DMAP (V) 1.1 g” 4.77 mmol )», at room temperature for 1 hour. The solution was washed with aqueous 101180, 708 and a saturated aqueous solution of sodium bicarbonate, then J plot concentrated saline, and then dried by anhydrous magnesium sulfate. The crude product was then purified by 0 flash chromatography using dichloromethane as eluting on a silica gel bed to yield the title compound (product = to Bg 7077).

0 no 1 H NMR (400 MHz, CHLOROFORM-D): 6.905 (m, 1H), 7.08 (dd, J=5.08,391 Hz, 0 1H), 7.26 (t, J =10.35 Hz, 1H) , 7.49 (m, 1H), 7.56 (dd, J = 3.71, 1.37 Hz, 1H), 7.63 (dd, J=5.08, 1.37 Hz, 1H), 7.78 (dd, J = 6.35, 2.83Hz, 1H Step Nig-(4-[recyclohexylmethyl)amino] {eds =F leuvene-?-e-sulfonamide: Hor BeSO NH 5 0 137 was stirred - (4-fluoro- 7- Nitrophenyl)thiophene -?- sulfonamide (VT) (By 0751 mmol)” and cyclohexylmethylamine (20 40” mm TA mmol) in ? mL of 3 containing TEA (0.0 00 mL “TY, + mmol)” under 0 °C for 4 hours. The solvent was evaporated, after which the crude product was dissolved in EtOAc, then this product was washed with a solution of 908 (KHSO4 and a saturated solution of sodium bicarbonate” and a saline solution, Se, and then the product was dried with anhydrous magnesium sulfate. The product was also purified. rl crude by flash chromatography using hexane/21086 with VY ratio on a silica gel substrate (product = 0 h (or 'H NMR (400 MHz, CHLOROFORM-DY): 1.03 6 (m, 2H), 1.26 (m, 3H), 1.61 (m, 2H), 0 (m, 2H), 1.82 (m, 4H), 3.13 (dd, J = 6.64, 5.47Hz, 2H), 6.46 (m, 1H) , 6.82 (d, J = 1.76 9.18Hz, 1H), 7.05 (dd, J = 4.98, 3 81Hz, 1H), 7.40 (dd, J = 9.18, 2.54Hz, 1H), 7.47 (dd, J

0 m7 1.37Hz, 1H), 7.59 (dd, J =5.08, 1.37Hz, 1H), 7.73 (4 J = 2.73Hz, 1H), 8.17 (m, ,3.71 = 1H). |Step N23 — [*-amino-4-[recyclohexylmethyl)amino]phenyl)thiophene-?7-sulfonamide. 0 8 H nH D+ TI NG, Dy N 07 8 by © 5 NH MH : : 0 0 dissolved 18 - 41 - [(cyclohexylmethyl)amino] -?-nitro {dd thoevine -?- sulfonamide (Te) pH 1,197 mmol) in 0 ml of 0/11 in nitrogen medium. Tin chloride (TI dihydrate (AY) in YT mmol) was added”; With the solution stirred under room temperature for 1 hour. Another amount of tin chloride, I 0 dihydrate 170 (pH 7560 mmol) was added, and the solution was stirred at room temperature overnight. The reaction mixture was hydrated by adding a saturated solution of sodium bicarbonate under Jr dor yd 2 and then 3 extraction of the solution twice by “EtOAc M washing J sls. Concentrated saline and aiid by anhydrous magnesium sulfate. The product was used directly for step f= without further purification (product — 00 BG048) MS (ESI) (M+H)+366.14.0 Example?: t=] - < -butyl - 1-(cyclohexylmethyl)-151-ju imidazole—o—yl]—N—methylthiophene-?-sulfonamide:

-and*- of N Cc Step A: 7< - t —Y] — butyl -1-(cyclohexylmethyl) = mH pazimidazole -0 yl] -5 <- methylthiophene - ?- sulfonamide boa a l of 0 0 Followed the procedures for Step A in Example 1” using 18-mr-amino-4-[(cyclrofaxylmethyl)amino]phenyl)N = methylthiophene-7-sulfonamide (10 pH 707 mmol) (for method of preparation, see the following steps in “c” d)” and trimethyl acetyl chloride (+4 ml” 777 mmol) in ¥ ml of .DCE The product was purified by reverse-phase HPLC using Yo-7080 from a mixture of 0 13:07 / 11:0 and then lyophilized 0 to obtain the title compound in the form of salt BU TFA (for product = p COTA (m, 5H), 1.61 (m, 2 H), 1.64 (s, 9 H), e' H NMR (400 MHz, METHANOL-D4): 1.22 (m, 1H), 1.74 (m, 2 H), 2.08 (m, 1 H), 3.29 ) 3 H), 4.43 (d, ]=7.62 Hz, 2 H), 7.15 1.67 (dd, J=5.08, 3.71Hz, 1 H), 7.33 (dd, J=8.98, 1.95 Hz, 1 H), 7.40 (dd, J=3.71, 1.37 Hz, 1 | H), 7.55 (d, J=1.56 Hz, 1 H), 7.81 (dd, J=5.08, 1.37 Hz, 1 H), 7.85 (d, ]=8.98 Hz, 1 H);

0 nod

MS (ESI) (M+H)+446.1; Anal. Calcd for C23H31N302S82 + 1.5 TFA + 0.1 H20" C, 50.49;

H, 5.33; N, 6.79. Found: C, 50.55; H, 5.39; N, 6.76. Step B: N — (6-fluoro —¥— nitrophenyl) —N— methylthiophene - ¥= sulfonamide. a 5 NO, mA] DL NO, Ir — ho F F 0 A solution of 17-(4-fluoro-7-nitrophenyl)thiophene-7-s_levonamide 001 (771) was added. mmol) in MDF (V (ml) L) a cold stirred solution at 0°C containing DMF (¥ ml) in NaH (7070 derivative in oil (Yo) in Ham »0487 mmol) And in a medium of nitrogen. The solution was stirred under (dads Yu. ad ¢ Jr dor yd m. Drops of methyl iodide were added) ve 540 ml; 87 mmol) with the solution being stirred at room temperature 0 (Taal) hours. The reaction mixture was hydrated below zero by the slow addition of a saturated solution of. NHUCL as the solvent was evaporated in vacuo, and the crude zl was dissolved in 8:01 C, then washed with a saturated aqueous solution of sodium bicarbonate, then with a concentrated saline solution, and then dried by anhydrous magnesium sulfate. The product was purified by flash chromatography using dichloromethane as an eluate on a silica gel bed to obtain the product mentioned in heading YA) with (Jove 1 11) NMR (400 MHz, CHLOROFORMD): 3.22 56 (s). , 3H), 7.10 (dd, 124.98, 3.81Hz, 1H), 7.26 (dd, J=3.91, 1.37Hz, 1H), 7.56 (m, 1H), 7.63 (dd, J = 5.08, 1.37Hz, 1H) , 7.69 (dd, J = 6.44, 2.73Hz, 1H).

-;1-0 thiophene - = sulfonamide 8 . ih {nf oe Hello,

F | NH - using 14-(4-fluoro-7-nitrophenyl) of followed the procedures in step c in the example mmol)”; Methylcycline TNT (Br (001)©) Methylthiophene-7-sulfonamide -<7 0 ml 4174 mmol 05 (0 0 mmol TEAS)” + TVR hexylamine (0 06 ml) The product was used directly in the next step without any purification on eToh .ml Vv 3 (F084 BG 11 = column chromatography. (for 1 product)

H NMR (400 MHz, CHLOROFORM-D): 0.98 § (m, 1H), 1.04 (m, 1H), 1.20 (m, 1H), 1.66 (m, 2H), 1.75 (m, 2H); 1.81 (d, J = 12.50Hz, 2H), 3.12 (m, 2H), 3.16 (5, 3H), 6.80 00 (d, J = 9.37Hz, 1H), 7.09 (dd, J = 4.98, 3.81Hz, 1H), 7.37 (dd, J = 3.81, 1.27Hz, 1H), 7.42 (dd, J = 9.28, 2.64Hz, 1H), 7.59 (dd, J =4.98, 1.27Hz, 1H), 7.65 (d, ] = 2.54Hz, 1H), 8.20 (m, 1H). Thiophene -?- sulfonamide 0

tA “ O o / / Dry Orig Ne — BH ) followed the procedures for step d in Example 1 using —N 41-[(cyclohexylmethyl)amino]-3-nitro { Job -30-methylthiophene (=Y=sulfonamide VT) by Hm06©r; ml) and tin chloride dihydrate (XY) IT 45 ? neighborhood of 0.87 XY mmol). The product was used directly for step A without further purification. 111 = pally mg (P44 MS (ESI) (M+H) +379.97.

0 nomal Cav -1(-butyl-?- -butyl-151-jo imidazole =0—yl)-17-methylbetzine sulfonamide. 7a §© Step A: 17 - -1(benzyl -?- -butyl -151-bizimidazole =0= yl —N— methylbenzenesulfonamide 0 OH Of $A here 1 Ni 3 followed the procedures for Step A in Example = using 18-[©-amino-4-Jy] mexylmethyl)amino]phenyl)N=methylbutynsulfonamide IT AA (mmol)”; and 0.0 mL tri(0-methylacetyl chloride) 1.737 mM DMAP (Jae (0 mM Te) in 0 mM dichloromethane. The product was purified by HPLC. Reverted phase using 0-70 70/8 (HO / CHRON) mixture and then lyophilized to obtain the title compound as the corresponding TFA salt (product = YA mg (JOYA)

0 -¢¢-— 1 H NMR (400 MHz, METHANOL-D4): 1.625 (5, 9H), 3.21 (5, 3H), 5.93 (5,2 H), 7.09 0 (m, 2H) , 7.12 (dd, J=8.98, 2.15 Hz, 1 H), 7.32 (m, 4 H), 7.48 (m, 4 H), 7.57 (dd, J=1.95, Hz, 1H), 7.62 (m , 1H); MS (ESI) (M+H)+ 434.1; Anal. Calcd for C2sH27N302S + 0.59 TFA + 0.2 HzO: C, 55.95; H, 4.86; N, 7.04. Found: C, 55.90; H, 4.85; N, 7.06.1.4 0 Step TNC (4-fluoro-*7-nitrophenyl)benzene sulfonamide: Ni 3 3 0 ; 2 ant NO, pg:8 “OX Ae 3 iE fluoro-7-nitroaniline (?gram” 17.8 mmol) was dissolved in 0 0 mL of pyridine It contained a catalytic amount of DMAP, and benzenesulfonyl chloride (1.37 mm 7 mmol) was added, and the solution was stirred under room temperature for ? hours. Then, 1 2 evaporation of the solvent” in mm, the crude product of EtOAc was dissolved, washed (KHSO, %o J shoes, and a saturated solution of sodium bicarbonate” and pyrene” and then dried by anhydrous magnesium sulfate. The product was purified by chromatography Flashing with hexane/8:06 at a ratio of 0:7 on a bed of silica gel (product = YE 04g g). 1

H NMR (400 MHz, CHLOROFORM-D): 7.09 56 (m, 1H), 7.18 (dd, J= 9.96, 8.98 Hz, 1H), 7.40 (m, 1H), 7.48 (m, 2H), 7.58 (m , 1H), 7.71 (dd, J = 6.25, 2.73Hz, 1H), 7.76 (m, 0 2H). Step h: N - (€- fluoro-?- nitrophenyl) —N- methyl betzine sulfonamide:

0 and 2 6 a a d HLH ao, O_o. FX PX F F Followed the procedures for step b in the oF example using SN (8 = fluoro-7-nitrophenyl)b-sulfonamide 1)g” 2.77 mmol)” NaH (9010 dispersed in (et VT) (Gry 7 mmol)” and methyl iodide (1.711 ml” 5.17 mmol) in Yo ml of DMF [fe] and aad ok produced by flash chromatography using dichloromethane as eluting on a silica gel bed (product = Ayo Mahji (OVA) 1 H NMR (400 MHz, CHLOROFORM) -D): 3.198 (s, 3H), 728 (m, 1H), 7.51 (m, 1H), (m, 2H), 7.57 (m, 1H), 7.65 (m, 2H). 7.54 step D:—N ]€— (Bazyl (geal == nitrophenyl] —N—methylbenzene sulfonamide. 2 A 1 Le ar NO, 5 Og — ne F 2 SON Followed the procedures for Step C in Example 0) using N-(4-fluoro-7-nitrophenyl) “N=methylbutyzensulfonamide VY) with a pH of 1.775 mmol); benzyl amine (0,107 mL 776 mmol)” and 7858 (00 0.0 mL” 44 7 mmol) in ¥ mL of EtOH pall was used directly in step 3 without further purification mull) = 4p (F084

_ Ed P 2 1

H NMR (400 MHz, CHLOROFORM-D): 7.17 ,)3H), 4.56 (d, J = 5.472: 2H), 681© (d, 1 = 9.18Hz, 1H), 7.34 (m, 3H), 7.40 (m, 3H), 7.49 (m, 2H), 7.57 (m, 1H), 7.60 (m, 1H), 7.64 (dd, J = 4.30, 1.95Hz, 1H), 8.47 (m, 1H) ). Methylated N= amino-4-[recyclohexylmethyl)amino]phenyl)-*[ —N in step benzenesulfonamide. 1 q 1 a> 0-8 NO, i NH,

J are 2 no = X

NH NH

18-[4-Jj)amino)-7-nitrophenyl] N=methyl po-sulfonamide (40 g) was dissolved; 4, , + mmol) in Vo mL of P2:08 content to a catalyst amount of 7001 0/00. The solution was shaken in a Parr hydrogenation apparatus in a medium of hydrogen (under a pressure of 0 406 psi) at room temperature for ; hours. The solutions were then filtered through the Celite layer and the solvent removed by evaporation. The product was used directly in Step A without further purification. (Product = AA BG 088( 0101136797 MS (ESI) .example tf =e -7) -N-butyl-1-(cyclohexylmethyl)-151-ju imidazole -# - yl] - Vo 3 8,9 - Trimethyl Iso and Xazole -6-sulfonamide

0 od TI ' pn ! + 0 2 Step A: N - [?- -butyl -1-(cyclohexylmethyl) = ju —HY imidazole - etd -4- trimethyl Isoxazole - 0 WN [Lo : A 0

HN bl ass MN

CH{ECA

N pepest 1 N-imidazole jv -111 methyl- N= (cyclohexylmethyl) -1-d stirred ?- + - butyl co mmol) (for the method of preparation see the steps Next: 111 Bahm TO) Amen =o

Soa y A 0 ) d) Hm f , t_ dimethyl ir and xazole _ 4-sulfonyl chloride ‘= mmol) in an amount of ? ml of dichloromethane containing catalyst 5+, overnight at room temperature. The DMAP was then evaporated using 4 — .8 O 968 Sal-phase HPLC mixture as the solvent; then the product was purified by 0 31.0 and then the product was lyophilized to obtain the title compound in the form of salt. / 0:07 (JOVY) (product = 44 mg BLL TFA 1

H NMR (400 MHz, METHANOLDx4): 1.21 § (m, 5 H), 1.58 ( 2 H), 1.65 (s, 10 H), 1.74 (m, 2 H), 1.88 (s,3 H), 2.08 ( m, 1 H), 2.33 (5, 3 H), 3.31 (s, 3 H), 4.46 (d, 1-1

Hz, 2H), 7.47 (dd, J=8.98, 1.95Hz, 1 H), 7.68 (d, J=1.76 Hz, 1 H), 7.91 (d, J=8.98 Hz, 1 0

. m - H); MS (ESI) (M+H)+ 459.2;Anal.

Caled for C2¢H3aN4OsS + 1.6 TFA +02 H20:C, H, 5.63; N, 8.69. Found: C, 50.70; H, 5.65; N, 8.81. | ;50.68 Step B: Methyl (4-FluorYmnitrophenyl) Karamat: 0.0 ER NO, “°F TX a.

HN NO, F drops of methylchloroformate 17.7 (TY) mmol) were added to a solution cooled at 0 °C containing dichloromethane (Ye mL) and 4-fluoro TT nitro aniline 04.7 cpl (YE,10 mmol)” and 0158 010 (Jo YO) mmol). The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with hydrochloric acid (ZM) and pyrene (M.Ado) using 0-aqueous magnesium sulfate. and € 5 cg 3S and use the product directly in the next step without further purification (product = Yo,0 g 20945). 1 H NMR (400 MHz, CHLOROFORM-D): 3.81 5 (s, 3 H), 7.02 (s, 1 H), 7.23 (m, 1 H), (d, J=8.59 Hz, 1 H ), 8.17 (dd, J=6.35, 2.64 Hz, 1 H). 7.72 Step C: methyl 47-[(cyclohexylmethyl)amino]—F—nitrophenyl)carbamate: LOO i.e. Sn Fun 10 HN F NH of 1

- - and ;- (Ir methyl (4-fluoro-©-nitrophenyl) carbamate) 1 g » 4.77 mM 0 moh (Jr YO BOH ml » 5.10 mmol) was stirred in + VF) and cyclohexylmethylamine h. YE was concentrated for a period of Vo under TEA (1 mV mL dpe) on Yoo, and then that substance was washed in EtOAc solvent, then the remaining substance was dissolved in © 10150, in a saturated solution of bicarbonate (pd pall) and pyrene; then dried using anhydrous magnesium sulfate. The crude product was also purified by flash chromatography using hexane/M 8:08 at a ratio of 4:1 on a silica gel substrate. (product = 001 gm; (Jovy 1

H NMR (400 MHz, CHLOROFORM-D): 1.04 § (ddd, J = 24.02, 12.11, 2.93Hz, 2H), 1.25 (m, 3H), 1.69 (m, 2H), 1.76 (m, 1H), 1.79 (m, 1H), 1.83 (m, 1H), 1.86 (m, 1H), 3.14 0 (dd, J = 6.44, 5.66Hz, 2H), 3.78 (s, 3H), 6.46 (m, 1H), 6.84 (d, J = 9.37 Hz, 1H), 7.63 (m, 1H), 8.05 (d, J = 2.54 Hz, 1H), 8.09 (m, 1H). Amino-4-[(cyclohexylmethyl)amino]phenyl)carbamate: =P} Step D: Methyl Bacham Ser Color: hg NO, b NH,

TL NH ro)nitrophenyl)carbamates mr Methyl 47-[(cyclohexylmethyl)amino] No mL of 8:086 containing a catalytic amount of Tr mMol) was dissolved in an amount of THEY grams” in a medium of Parr hydrorhene, and the solution was shaken in a hydrogenation apparatus of the type . 0

0. .

. (under a pressure of 46 psi)” at room temperature overnight. The solution was also filtered through a layer of an©, the solvent was removed by evaporation, and then the product was used directly in the next step without further purification (product = 460 mg 0055). MS (ESI) (M+H)+ 277.9

0 step h: instance [?-; -1-butyl- (recyclohexylmyl = THY bisimidazole —o— yl]carbamate.

A O° HM NH, HN No CL — "CA oi 0 Methyl (©-amino-4-[(cyclohexylmethyl)amino] {Jd carbamate) 100 dissolved in Qu7 ,47 mmol)”; DMAP (01 mmol ACA) in an amount of 0 ml yo dichloromethane. Drops of trimethyl acetyl chloride (8) (de lala, mmol) and the solution was stirred under room temperature for one hour. The concentration (cpl) was suppressed and the remaining substance was divided into two parts and each was dissolved in ?ml of I ACOH in a tightly closed tube. The solutions were heated below 101 degrees M using a Personal Chemistry Smith Synthesizer microwave for three time intervals sds V0 each 301 min x TY 30 min).Then the contents of the two tubes were collected and Ge was removed.

solvent”, then the residue was dissolved from BIOAC and washed with J gles saturated with sodium bicarbonate and pyrene” and then dried by anhydrous magnesium sulfate. The crude product has been purified

-H1-0 using a flash chromatography in the presence of a mixture of dichloromethane/diethyl ether: 37657 (Product 199 BG 1:3) with a ratio of 1 H NMR (400 MHz, CHLOROFORM-D). ): & 1.08 (m, 2H), 1.18 (m, 3H), 1.54 (s, 9H), 1.65 (m, 1H), 1.69 (m, 2H), 1.73 (dd, J = 5.96, 3.22 Hz, 2H ), 2.02 (m, 1H), 3.78 (s, 3H), 4.10 (d,J=7.42 Hz, 2H), 6.64 (m, 1H), 7.25 (d, J = 8.79 Hz, 1H), 7.39 (m , 1H), 7.59 (d, ©

J=1.76 Hz, 1H). Bz THY — Jt N= (cyclohexylamine) -1- step f: ?- — butyl imidazole —0— amine:

Ou pO 0 p e

HN 5 HN 0: a — )m —o= pyrimidazole HY = (cyclohexylmethyl) -1- methyl [?- + -butyl 0] dissolved

Gp io ml of 110 below 01 degrees in the neighborhood of 1.88 mmol) in (To) yl carbamates cdr ¥510 (Jal JIM) atmosphere of nitrogen. A mixture of dichlorochloric acid was added a minute. Vo slp Dio and the solution was stirred under col hb (mmol) in the form of 05 and then slowly an amount of 210 pH (4.80 mmol) of The solution thickens with stirring, at room temperature, overnight. The reaction mixture was oxidized under Siw m by adding MeOH (0 ml) and then an amount of water 10 ml. J was diluted with BIOAC and washed with a saturated solution of sodium bicarbonate and pyrene.

0 Because the drying process was carried out using anhydrous magnesium sulfate. NEP was evaporated and the product was used directly in Step A without further purification (Product = 544 g 7057). 'H NMR (400 MHz, CHLOROFORMDY): 5 1.08 (6 2 H), 1.17 (m, 3 H), 1.54 ( 9 H), (m, 2H), 1.67 (m, 2H), 1.72 ( m, 2 H), 2.02 (m, 1 H), 2.87 (s, 3 H), 4.06 (d, J=7.62 1.64 Hz, 2H), 6.60 (dd, /=8.69, 2.25 Hz,1 H ), 7.00 (d, J<1.76 Hz, 1 H), 7.12 (d, /=8.59 Hz, 1 © H).

M Laj Example ‎Tie “- [?- ? -butyl-1-(cyclohexylmethyl)-151-bizimidazole-5-yl]-31,?—trimethyl-159-epimidazole—€—sulfonamide. N 8 1 | 8 CLA Ter N 0 2 0 0 Emit the excretions of Step A in Example -4” using ?- + - butyl (JS SIS) -1-methyl) N= methyl - 111- ju imidazole -#-amine (1171 TY)mmol)” and 1,71- dimethyl-111-imidazole-4-sulfonylchloride (Yr) in 0.144 mmol DMAP (catalytic) in ¥ mL of dichloromethane. The ell was purified by reverse-phase HPLC using 71 - 9080 of (HO / CHsON and then this r = 01 was lyophilized to obtain the title compound 3 as the corresponding TFA salt) = = Except 4 =( (Yona 1

H NMR (400 MHz, METHANOL-Ds): § 1.22 (m, 5 H), 1.62 (m, 2 H), 1.64 (s, 9 H), 1.67 (m, 1 H), 1.75 (m, 2 H) ), 2.09 (m, 1H), 2.34 (s, 3H), 3.28 (s, 3H), 3.61 (s, 3H), 4.43 (d, J=7.62 Hz, 2H), 7.43 (dd, J=8.98, 2.15 Hz, 1 H), 7.51 (5, 1 H), 7.66 (d, J=1.95

Hz, 1H), 782 (d, J=9.18 Hz, 1H); MS (ESI) (M+H)+ 458.2; Anal. Caled for m C24H3sNs02S + 1.7 TFA + 0.1 1150: C, 50.38; H, 5.69; N, 10.72. Found: C, 50.39; H, 5.73; N, 10.73.

1 1e Mal 7:,-1[--butyl-1-(cyclohexylmethyl)-1171-ju imidazole —0— yl] N— 8,9,1-tetra Jae -13-pyrazole-6-sulfonamide. . yba oo al 0-0 0 You followed the procedures for step a in Example -4” using ?- + -butyl-1-(cyclrofaxylmethyl)=N—methyl-111-ju imidazole -- Amin (SAY er TT mmol)» W?; d-trimethyl-111-pyrazole-4-sulfonyl chloride (Yo) gm” mM VEE (J DMAP (catalytic) in 7 mL of dichloromethane. The product was purified using HPLC With the sell phase and in the presence of Yo = 7080 from the mixture (HO CHCN) then the product 0 was lyophilized to obtain the title compound in the form of the corresponding M788 salt (product = 49 (of 0 1 H NMR (400 MHz, METHANOL-D4): § 1.20 (m, 5 H), 1.56 (m, 2 H), 1.65 (6 9 H), 1.67 (m, 1 H), 1.74 (m, 2 H), 1.80 (s, 3 H), 2.08 (m, 1 H), 2.16 (s, 3 H), 3.21 (5, 3 H), 3.69 (s, 3 H), 4.44 (d, 127.81 Hz, 2 H) , 7.38 (dd, J=9.08, 2.05 Hz, 1 H), 7.62 (d, J=1.56

Hz, 1H), 7.84 (d, J=8.98 Hz, 1H); MS (ESI) (M+H): 472.2; Anal. Caled for 5

C2sHz7NsO28 + 1.2 TFA + 0.4 1100: C, 53.45; H, 6.38; N, 11.37. Found: C, 53.50; H, 6.38; N, 11.29.

Example CV N - [1- ¢ -butyl -1- (cyclohexylmethyl) = Joab pm =H =0— yl] benzenesulfonamide: methyl il N 95 0 step: «- [?-; -butyl-1-(cyclohexylmethyl)-151-Jo imidazole-0-yl]benzene sulfonamide SR FORA O 2 added To 4 4 (DMAP, + mmol); Then trimethyl acetyl chloride (138 pg 89 mmol) at zero degrees to a solution of 13-(©-amino-4-[(cyclomexyl 0-methyl)amino] {ed betzin-sulfonamide) 08.1 pH” 0.8 mmol) (for the method of preparation, see steps B, C, D (WY) in an amount of dichloromethane of tr ml. The mixture was stirred for 0 hours at room temperature, and after the solvent was evaporated The residual substance was dissolved in 7,1-dichloroethane (00 Jr 0 x) in a Teflon-coated Teflon © ll test vessel and the vessels were irradiated with a microwave for two hours at ae VV and after

© one .: That the combined reaction mixture was diluted with 100 (BtOAG) (mL); Then the mixture was washed with sodium hydroxide (a 01(2N) and a saturated solution of sodium chloride 10(mL); then the mixture was dried with sodium sulfate. After filtration and evaporation, the residue was purified by HPLC using an EtOAc mixture [ OLS in a ratio of 1:1 on a bed of 0 silica gel to yield 0A Y g (OAR) of the title compound as a white solid; this is SM partly converted to the TFA salt ‏

MHz, CD30D: 5 1.18 (m, 5 H), 1.55 (m, 2 H), 1.59 (s, 9 H), 1.65 (m,1 H), 400 (mm (m, 2 H) , 2.03 (m, 1 H), 4.34 (d, J=7.42 Hz, 2 H), 7.20 (d, J=9.18 Hz, 1 H), 7.44 (m, 1.71 H), 7.53 (m, 1 H), 7.58 (s, 1 H), 7.70 (d, ]=8.79 Hz, 1 H), 7.76 (d, J=7.42 Hz, 2 H).MS 2 (ESI) (M+H)+ = 426.1.Anal.

Calcd for C24H3iN3025+1.10 TFA+0.10 H20: C, 56.92, H, 0 N, 7.60. Found: C, 56.95; H, 5.92; N, 7.56. ;5.89

Step B: 8< — (4-fluoro--nitrophenyl)benzene sulfonamide:

HN NO, Ole H Ha Alb" More 0 1

pyrenesulfonyl chloride (0.1 mL col V,VE 64 mM (Js) was added to a solution of ¢-- Ye fluoro-oro-aniline LY g 40 mmol) in pyridine (40 ml) at a temperature of 48 °C. The reaction mixture was stirred for two days at room temperature.” After evaporation of the solvent, the remaining material was dissolved in a quantity of BIOAC (Jo 5000), and then that material was washed with water (Je 0) and hydrochloric acid (ro) sly ( Je (50 XY) @N) and an aqueous solution

—-oV- 0 saturated SpSy sodium (Jr on XY) then a saturated aqueous solution of NaCl (ov XY mL); And then that substance was dried by sodium sulfate. After filtration and concentration 3 obtain 1 Y 0 1 g) 1.Yo from a brown solid to fail the title compound. 1 HNMR (400 MHz, ©0:01(:6 720 (m, 2 H), 7.44 (m, 1 H), 7.52 (m, 2H), 7.61 (m, 1 H), © (dd , J=6.25, 2.73 Hz, 1 H), 7.81 (m, 2 H). 7.75 Step C: 133 - 41 - [r(cyclohexylmethyl)amino] =¥= nitrophenyl)benzenesulfonamide.Yoo © H . : 0 § P F 9 9 0 cyclohexylmethylamine (TEA) ml » 7.17 g » 77.7 mmol) was added to a mixture of 17-(4-fluoro -7-nitrophenyl)butylate sulfonamide (VT) 1.1 mmol) in 0 ml of 122086/HO in a volumetric ratio of 1:1 at room temperature. The reaction mixture was heated for EA for 1 hour under EE °C and the ob mixture was allowed to cool to room temperature 5 was concentrated to a small volume and subsequently extracted by EtOAc as of Vo and the crude product was obtained using MPLC and by a mixture of Hexane/EtOAc in a ratio of 4:1 on a layer of silica gel to obtain the title compound in the form of an orange-red solid (product = YL Ve g (JV)

-0 hm 0 1 0

HNMR (400 MHz, BaS: § 1.05 (m, 2 H), 1.24 ) 3H), 1.72 (m, 6 Hy 3.12 (dd, -

J=6.64, 5.47Hz, 2H), 6.23 (s, 1H), 6.79 (d, J=9.18 Hz, 1H), 7.36 (dd, /=9.08, 2.64 Hz, 1H), 7.48 (m, 2 H), "7.58 (m, 1 H), 7.63 (d, J=2.54 Hz, 1 H), 7.72 (m, 2 H), 8.14 (s, 1 H). ) vinyl) benzene [perl Step D: »8-(©-amino-4-[recyclohexylmethyl)sulkonamide) ©

Qa GUT Count 0 1 0 0 8 of of 8-(4-[(cyclohexylmethyl)amino]-7-nitrophenyl)btzensulfonamide 00 9611 ml)” was hydrogenated with catalysis by Yo 0 (mmol) in ethyl acetate (4.77 cm TV) lb/inch in a shaker of Th = 460 g) under hydrogen pressure of CIP (+0) and after Celite 1 hour at room temperature. After filtration through layer 310 for Parr Model 0 of the title compound in the form of a solid with color (WV +0) concentration, 4 grams of light yellow were obtained, and these were then used in step A below. Further refinement. 4 H), 2.86 (d, J=6.64 Hz, 2 H), 3.33 (s broad, 3 H), 6.30 (s broad, 1 H), 6.33 (dd, J=8.30, 2.44 Hz, 1H), 6.41 (m, 1 H), 6.56 (d, J=2.34 Hz, 1 H), 7.41 0 2107.52 1 (m,1 H), 7.70 (m, 2 H).MS (ESI) (M-H)+: 359.89.

An example

0-OH-3-[1H (cyclohexylmethyl)-7-ju -151- Jl imidazole -#-yl]bensulfonamide.:

QUI

1 z + most of it

Be mmol) then propionyl chloride (0.8) 1000 mM 1.0 (0% Vo) DMAP added phenyl crit) [od amino-4-[(cyclohexylmethyl) or} NUS mol) to 0 mmol) of dichloromethane (10 ml) under 1.5 pH VAT sulfonamide 0 m. The mixture was stirred for 10 hours at room temperature, and after evaporating the melt for 1 hour at a temperature of 10 ml, then heated for 10 minutes, the remaining substance was dissolved in acetic acid, then it was washed (EtOAc (Jr 001) M. and after concentration 5 dilution of the remaining substance with A 01 (of sodium chloride ete ml); Purification of the crude product using

VoV,V on a layer of silica gel) to obtain a 9:1 ratio of EtOAc (hexane/MPLC) and this fraction has been converted to slag of the title compound in the form of a solid (SOV) in molasses. TFA salt HNMR (400 MHz, CDsOD): 1.12 (m, 2 H), 1.21 (m, 3 H), 1.48 (t, J=7.62 Hz, 3H), 1.60 m (m, 2 H), 1.68 (m, 1 H), 1.73 (m, 2 H), 1.90 (m, 1 H), 3.18 (q, J=7.49 Hz, 2 H), 4.19 (d, J= 7.62 Hz, 2H), 7.24 (m, 1H), 7.47 (m, 2H), 7.56 (m, 2H), 7.71 (d, J=8.98 Hz, 1

H), 7.79 (m, 2H). MS (ESI) (M+H): = 398.1.

1 4

Taq mal [d= -8-imidazole ju =H = (cyclohexylmethyl)-7-isopropyl-1[-N sulfonamide op

QUT

Fen 0 N amino-4-[(cyclohexylmethyl)amino] =v} -N using (A followed the example procedure 0 mM VY DMAP VO)mmol)» 1 5. (of 187,1(phenyl)butenesulfonamide mmol)” and © 7:01 Wm (10 ml). (1575 mol)” and isobutyl chloride (00.7 mg).

YA, - gad (©1). (d, J=6.83 Hz, 6 H), 1.60 (m, 2), 0 1.72 (m, 3 H), 1.88 (m, 1 H), 3.62 (m, 1 H), 4.25 (d, 127.62 Hz , 2 H), 7.25 (dd, 128.88, 2.05 Hz, 1H), 7.48 (m, 2 H), 7.57 (m, 2 H), 7.73 (d, ]=8.98 Hz, 1 H), 7.80 (m, 2 H).MS (ESI) (M-+H)+ = 412.1.'Noe eg Bz THN = methylcyclopropyl)-1(((cyclohexylmethyl)-?--1] - 3 0 imidazole -©- yl]benzene sulfonamide:

=-1y- 0 $0 0

Diisopropylethylamine (01.4.7 g” AY mmol) was added to =v} NE amino-4-[(cyclohexylmethyl)amino]phenyl)benzenesulfonamide (40.7pg POET

mmol)” and (-1-methylcyclopropane carboxylic acid (A), 04 BG (1, mmol)

© in DMF (e.g. ml) at 0 °C with stirring for 1 min. HATU (YE, 8) was added in District 658, ; mmol) and the reaction mixture was stirred for 4? an hour at room temperature.” Then, the mixture was diluted with 1-(ml) water; It was extracted with XY (EtOAc 50 mL).

The combined organic phases were washed with sodium chloride (V0 ml) and then diluted with anhydrous sodium sulfate. After filtration and concentration, the substance was dissolved for preservation in acid

0 acetic 01 (ml) with heating for 1 hr under As 0°C. After evaporation of the solvent, a lyophilization process was carried out on an amount of acetate salt of 53.7 h, and the rest of the salt was diluted with 06:8 (Jo 001) and then washed with hydrate and sodium oxide (@N)

01 (ml). and with a saturated solution of sodium chloride (Je 01 XY) and then dried with anhydrous sodium sulfate. After filtration and evaporation, 144.9 pH was obtained

(048 = title compound in the form of a free amine (of the total product vo

HNMR (400 MHz, CD:0D): 0.89 (m, 2 H), 1.10 (m, 4 H), 1.21 (m, 3 H), 1.45 3

H), 1.55 (d, 2 H), 1.69 (m, 3H), 2.08 (m, 1 H), 4.13 (d, 17.62 Hz, 2 H), 7.01 (dd, 1-879,

1.95 Hz, 1 H)) 7.25(d, J=1.95 Hz, 1 H), 7.35 (d, J=8.79 Hz, 1 H), 7.40 (t, ]=7.62 Hz, 2

2 Mada H), 7.50 (t, J=7.42 Hz, 1 H), 7.68 (d, J=7.42 Hz, 2 H). MS (ESI) (M+H)+=424.1. Anal. Calcd for C24H2oN3028+0.4 AcOH+0.10 H20: C, 65.92; H, 6.98; N, 9.45. Found: C, H, 6.89; N, 9.09. ;66.01 Ex: 01-1[-<«(cyclohexylmethyl)-7-(1-(-dimethylpropyl) = THN bisimidazole —0— yl] - Benzene sulfonamide. oH Ola MN . 5 FCO followed the procedure of Example 01 using 14-=F}amino-4-[(cyclohexylmethyl)[selphenyl]ptyrenesulfonamide VAT) g” 1.90 mM mall); And acid? 160 mmol) in DMF (© ml) and then in acetic acid (01 ml). The crude product was purified using reversed-phase HPLC in the presence of YA. - 08 of the CH;CN /0Ht1 mixture to obtain an ad was added to the acid of Yo 01 from the title compound in the form of a white solid. 1 (t, J=7.52 Hz, 3 H), 1.20 (m, HNMR (400 MHz, (s, 6H), 1.68 (m, 1 H), 1.75 (m, 2 H), 1.97 (4 J) =7.62 Hz, 2 H), 2.03 (m, 1 H), 4.37 1.62 (d, J=7.62 Hz, 2 H), 7.23 (dd, ]=8.98, 1.95 Hz, 1 H), 7.47 (m , 2 H), 7.56 (m, 1 H), 7.59

11 2 (m, 1 H), 7.73 (d, ]=8.98 Hz, 1 H), 7.80 (m, 2 H). MS (ESI) (M+H)+= 440.2. Anal.

Calcd for C2sH33N3028+1.0 TFA+0.60 H20: C, 57.45; H, 6.29; N, 7.44. Found: C, 57.49;

H, 6.39; N, 7.35.

NY (eg HN = biotinyl) =F (dimenyl) = YY) Y = (cyclohexylmethyl)-1[-“benzimidazole —0—yl]-benzenesulfonamide. z

SUI

PEs ag la-amino [(cyclhexylmethyl)amino] } = N using 0 followed procedures ex. - 4-dimethyl (SY, Y mmol)” and 1.90 pH acid” VAST) phenylbutyrate sulfonamide

Ve (ATT) mmol)” and diisopropylethylamine 1,55 in vi (V0) betinoic acid 0 and then in acid (J + ©) DMF mmol) in 160 Bahm 77/8:1 (HATU mmol); phase-reversed HPLC ml). The crude product was then purified by 10 acetic acid (7014) from TAY to obtain HHO / 013:07 from mixture 7680 - T+ and using the title compound in the form of a white solid. 1

HNMR (400MHz, CDsOD): 5 1.19 (m, 5 H), 1.59 (m, 2 H), 1.65 (s, 6 H), 1.68 (m, 1 H,) Vo 1.74 (m, 2H), 2.04 ( m, 1 H), 2.67 (d, J=7.42 Hz, 2 H), 4.40 (d, 17.62 Hz, 2 H), 5.03 (s, 1 H), 5.07 (m, 1H), 5.60 (m, 1 H), 7.23 (dd, ]=8.98, 2.15 Hz, 1 H), 7.47 ( 2 H), 7.56

. f (m, 1 H), 7.59 (d, J=1.56 Hz, 1H), 7.74 (d, J=8.98 Hz, 1 H), 7.80 (m, 2 H)*MS (ESD (M+) H)+ = 452.2.Anal.

Calcd for C26H33sN3025+1.2 TFA: C, 57.97; H, 5.86; N, 7.14. Found: C, 58.00; H, 5.74; N, 7.06. A.Y. Jie

-1[-3(cyclohexylmethyl)-?-(0-dimenacyl ich) = THY Bz

Imidazole —0— yl] 5< methyl-oj sulfonamide.

amide 0

NaH (4 © phm 70760 4 1.7 mmol) was added to a solution of 17-[?- + -butyl-1-(cyclohexylmethyl) = HY bisimidazole mom yl] . sulfonamide cage (0 YON in PUNE AE mol) in THF (VO ml) under zero degrees Celsius. After stirring for one hour, YO 3, A) Mel was added to (Jar) milliliter VAT, and the mixture was stirred throughout the labeling period at room temperature, then a saturated lon of sodium bicarbonate (0 ml) was added. The two phases were separated and the JU phase extracted by (Jo 01 XT) EtOAc as well as the combined organic phases were washed with sodium bicarbonate (XY 01 ml); Then these Vo phases were dried with sodium sulfate. After concentration, the residue was purified using MPLC and by a mixture of [OLS M8:08 in a ratio of 1:1 on a layer of silica gel to obtain 7 105 JOAN of the title compound and convert it to TFA is in the form of a white solid.

HNMR (400 MHz, SS: 1.20 (m, 5 H), 1.60 (m, 2 H), 1.64 ( 9 H),1.67 (m, 1)

H), 1.75 (m, 2 H), 2.07 (m, 1 H), 3.24 ( 3 H), 4.42 (d, J=7.62 Hz, 2 H), 7.26 (dd,

J=8.98, 2.15 Hz, 1H), 7.50 (m, 5H), 7.65 (m, 1H), 7.81 (d, J=9.18 Hz, 1H). MS (ESI) (M+H)+ = 440.2. Anal. Calcd for C2sH33N3028+1.20 TFA: C, 57.09; H, 5.98; N, 7.29.

Found: C, 57.07; H, 6.01; N, 7.25. 1 : 2 ° Example N= yl] =o-bizimidazole -81- Jd (cyclohexylmethyl) -?- -1[ -« methyl-benzene sulfonamide

Qh a

APS

0 “HY = (cyclohexylmethyl)-?-ethyl-1[-18 using VF followed ex. procedures 0 mmol); hydride YY petrimidazole -*- yl] betzine sulfonamide (81.7 pH 015 mM FAY, 8) pH 7010 L 1; mmol)” iodomethane (YAY) sodium (ml). product = 8.7 g 9074 as a white solid of salt (THF 1 0 mol) in

TFA

HNMR (400 MHz, CDsOD): E 1.20 (m, 5 H), 1.51 B J=7.52 Hz, 3 H), 1.65 (m, 2H), 9 1.70 (m, 1H), 1.76 ( m, 2 H), 1.95 (m, 1 H), 3.22 (q, J=7.62 Hz, 2 H), 3.27 (s, 3 H), 4.26

: A 8 (d, J=7.62 Hz, 2 H), 7.29 (dd, J=8.88, 2.05 Hz, 1 H), 7.50 (d, 11.95 Hz, 117(7.54 4Rs) 7

H), 7.67 (m, 1 H), 7.80 (d, J=8.98 Hz, 1 H). MS (ESI) (M+H)+ = 412.1

No Example [d= —0— imidazole jo -159- -?-isopropyl Joie [cyclohexyl -1] -« 0 ethyl-benzene sulfonamide TN They 90 N (cyclohexylmethyl)-7?-isopropyl[-1-17] using (VY followed example procedures MmMol 0155 AVA) with benzene-sulfonamide —o— Biz imidazole -111- Ole (AY Millimol)"; Yodo 1,943 0970760 (YE) and sodium hydride 0 (Yo Ae) have been converted into (Ar) = ml). Product Vo) THF in (Js m XN

TFA refers to a white solid representing salt 1

HNMR (400 MHz, CD30D): § 1.20 (m, 5 H), 1.51 (d, J=6.83 Hz, 6 H), 1.64 (m, 2 H), 1.69 (m, 1 H), 1.76 (m, 2 H), 1.93 (m, 1 H), 3.27 (s, 3 H), 3.67 (m, 1H), 4.31 (d, ]=7.62

Hz, 2 H), 7.28 (m, 1 H), 7.54 (m, 5 H), 7.68 (m, 1 H), 7.81 (d, J=8.98 Hz, 1 H). MS (ESI) 0 (M+H)+= 426.1.

Ae. An example would be BZ THN = cyclo-proyl (fie -1) cyclohexyl-yl-?--1[-1'-methyl-benzenesulfonamide. —N— imidazole -*-yl)] ,

GLI

FC

0 . [+] dtr-1(-7-(cyclohexylmethyl)-1[AN] using VF followed procedures ex. 747 pg 144,9(imidazole -#-yl]btzensulfonamide ju - 111- Cyclopropyl).

(or millimoles) and Yodo 797 DOT (volume (to) millimoles); and sodium hydride ml). Product = 7.7 no meat (/704). And you provided (VO) THF mmol (0.17 in 1 pH 48.97)

TFA turns the compound into a white solid representing a salt 0 " HNMR (400 MHz, CD:0D): N 1.19 (m, 4 H), 126 (m, 3 H), 1.34 (m, 2 H), 1.59 (5, 3

H), 1.71 (m, 5 H), 2.19 (m, 1 H), 3.26 (s, 3 H), 4.38 (d, J=7.81 Hz, 2 H), 7.29 (dd,

J=9.08, 2.05 Hz, 1 H), 7.50 (m, 1 H), 7.52 (m, 1 H), 7.55 (m, 3 H), 7.67 (m, 1 H), 7.83 (d,

J=8.98 Hz, 1 H). MS (ESI) M+H) += 438.2. Anal. Calcd for C2sH31N302S8+1.2

TFA+0.10 1120: C, 57.11; H, 5.67; N, 7.29. Found: C, 57.19; H, 5.74; N, 7.22. Vo

VY Jie

0 -14- -1,(,-7[ -< dimethylethyl) -0-[_tetrahydro—HY— pyrane -;- yl ju -151- [J imidazole —0— Yale]. Benzene sulfonamide. MN 87 3 of Step A:—N [?-1,= dimethylethyl) == [(tetrahydro—HY—pyran—t—0 yl) Methyl]-151-jo imidazole—0—yl]-benzene-sulfonamide. Qu 8 NH I JM N A Realiiing g ou N 0 ee - prk 5 OC 0 catalytic DMAP was added in one part with bivaloyl chloride YT (ml » 111 eq.) as successive drops to a solution that has been stirred and contains 18-=v]amino-4-[[(tetrahydroHY pyran-4-yl)methyl]amino]phenyl]-btzensulfonamide (Veo, XY) Baham (1.80 mm 0 mol) (for the method of preparation see steps go d) in MA01©11 (001 mL) at 0°C. The solution was stirred for 2 hours, then the solvent was concentrated and the remaining lead was dissolved in AcOH (¥ ml). The resulting solution was then heated below 1 Vou C for 0 sec using microwave radiation; Then concentrate the solvent. The material, ial, was re-dissolved in 8:06, then that substance, J los, was washed with sodium hydroxide (XY) IN with 11 concentrated saline solution, and then 2 dried by anhydrous sodium sulfate. After purification by

From 70950 = 01 using HPLC with subsequent further purification by BtOAG and using MPLC 0 pg 16,7 (in water the title compound was obtained in the form of a colorless solid MeCN product). 70 "HNMR (400 MHz, CD:OD) 1465 (m, 4H), 1.62 (s, 9H), 2.25-2.35 (m, 1H), 3.30-3.34 (m, 2H), -3.88 3.92 (m, 2 H), 4.43 (d, J=7.42 Hz, 2 H), 7.22 (dd, /=9.08,2.05 0 Hz, 1H), 7.43-7.47 (m, 2 H), 7.52 -7.56 (m, 1 H), 7.60 (d, J=2.05 Hz, 1 H), 7.75-7.80 (m, 3 H); MS (ESI) (M+H) += 428.0. Step B: 3 < - (4-fluoro--7-nitrophenyl) — benzenesulfonamide.

Or — gia. 1 in 0 catalytic DMAP was added in one part with betzine-sulfonyl chloride AAT (ml” 117 equiv) as successive drops to a stirred solution containing 4-fluoro-7-nitroaniline Vo gram” is 14.1 mmol) in pyridine (oY) mL) below zero degrees Celsius. The solution was stirred below zero degrees. for 30 minutes and then gradually warmed to room temperature. After 0 hours at room temperature, the solution was diluted with (Vo) EtOAc mm and then washed with water to (CH, (01 M) TLC if the organic layer was free of pyridine; then purification was carried out by ye

MPLC The solution was dried with anhydrous sodium sulfate; After purification by using 013:01, the title compound was obtained in the form of a gram yellow solid (VY) cal 9671 product.

AR 0 1 H NMR (400 MHz, CDCk): 587.21 (dd, J=10.15, 8.98 Hz, 1 H), 732-7.36 (brs, 1 H), (m, 1 H), 7.51 (m, 2H), 7.62 (m, 1 H), 7.77 (dd, J=6.25, 2.93 Hz, 1 H), 7.82 (m, 2 7.44 H). Step C:—N [ ©-nitro-4-[[(tetrahydr = HY pyran-4-yl)methyl] [sel© phenyl]-benzene-sulfonamide. Am Al 2 a 2 — 206 G : O | 0 was added 4-tetrahydropyranmethylamine (£TA) with 7.1 equiv) in P8:04 (10+mL) to a stirred solution It contains SN (4-fluoro-?-nitrophenyl)-betenesulfonamide 1 (g » 7.778 mmol) » and triethylamine (497, filling 1 equiv) in a mixture of 0 0/0 8106E11 in a ratio of 4: VO (1 mL) at room temperature. The solution was heated below 10 °C. all night” and then cooled to room temperature. Then, the cooled solution was poured into aqueous solution, and (XT) was extracted by means of EtOAc. The combined organic phases were also washed using pyrene and then dried by anhydrous sodium sulfate. Purification of the crude product was also carried out using MPLC and by the two grains/ 1 : 1 EtOAc to obtain the title confusing Vo in the form of a brightly colored al (0 VV, J (Yooh 'H NMR (400 MHz, CDCL): 146 - 141 8 (m, 2 H), 1.65-175 (m, 2 H), 1.90-1.98 (m, 1 H), 3.18-321 (m, 2 H) , 3.39-3.45 (m, 2 H), 4.00-4.04 (m, 2 H), 6.61 (s, 1 H), 6.80 (d,

0 except

J=9.18 Hz, 1 H), 7.38 (dd, J=9.28, 2.64 Hz, 1 H), 7.46-7.50 (m, 2 H), 7.56-7.60 (m, 1 H), 7.69 (d, J= 2.54 Hz, 1 H), 7.73-7.75 (m, 2 H), 8.10 (m, 1 H). [sel pyran-4-yl)methyl] —BY = amino == [[(tetrahydro —F] —N Step D: phenyl]benzene sulfonamide: Alyl IX FX NH A0 The procedures of step e were followed in the example ors using 18-or]nitro-4-[[(tetrahydr = 7-pyran-4-yl)methyl]amino]phenyl]-btzensulfonamide (0 VY, HB 1.97 mmol)” and a catalyst amount of C/Pd 90101 in (Je© +) EtOAc MS/LC analysis indicated that the compound was of high purity (more than 40 Yo and could Use it directly in step A. (product = % 01 Step A (product = 0 0) 0 C= Yio 1 Y 1 H NMR (400 MHz, CDC) 8 1.44 1.33 (m, 2 H ), 1.61-1.73 (m, 2 H), 1.81-1.88 (m, 1 H), 2.95 (d, J=6.64 Hz, 2 H), 3.37-3.43 (m, 5 H), 3.99 (dd , J=10.84, 3.42 Hz, 2 H), 6.27- (br.s., 1 H), 634-636 (m, 1 H), 6.42-6.44 (m, 1 H), 6.58 (d, J=2.34 Hz, 1 H), 7.40- 6.31 (m, 2 H), 7.50-7.55 (m, 1 H), 7.70-7.74 (m, 1 H). 7.44 0 Example: 0 #

0 Tv

8 - [7H17-dimethylethyl)-1-[zetrahydro-?-furaryl)menyl]-

1 benzimidazole—0—yl]-benzenesulfonamide.

2 il _N Fon 0 -1,1( -7[ dimethylethyl) -1-[zetrahydro-?-furanyl)jo -151-[Je 0 imidazole — 0— yl]benzene sulfonamide. Z methyl QUT il 1 n © - TX, © 0 0 Followed the procedures for Step A in Example (VY using 75 =v]amino-4-[[(tetrahydro-?-furanyl) Methyl[amino]phenyl]-btzensulfonamide (4/8,7 with a volume of » 1,777 mmol) (for method of preparation see next steps B & C) DMAP ¢(J—= ¥+) CHCLyy 0 recombinant and bivaloyl chloride (YY), + mL (“11 equiv)” filled with 7 mL of 80011. The crude product was purified by MPLC using a mixture of 06:2 and hexane at a ratio of 1:46 and the product was converted to Salt m17 analogues with iid by freezing. Product of title compound as salt VAY,Y = TFA in (0011) meat.

'H NMR (400 MHz, CD:0D): 5 1.60 (5, 9 H), 176-179 (m, 1 H), 1.89-2.04 (m, 22 2.18- 2.26 (m, 1 H), 3.64 -3.69 (m, 1 H), 3.84-3.90 (m, 1 H), 4.28-4.34 (m, 1 H), -4.53 m

m dgla (m, 1 H), 4.66-4.71 (m, 1 H), 7.21 (dd, J=8.98, 1.95 Hz, 1 H), 743-747 (m, 2H), 4.59 (m, 1H), 7.59 (d,J=1.95 Hz, 1H), 7.75-7.79 (m, 3H); MS (ESI) (M+H)+ = 7.52-7.56 .414.0 Step B: –N[*-nitro--[[tetrahydro-Y-furanyl)methyl]amino]phenyl]m AMT Sulfonamide. RM Clg z RA Ao, 5 fT 9 Nit a 0 Co© Procedure followed step 3 a eg Y 0 ¢ using —-N ) 4-fluoro-?1-nitro phenyl) — 1 betzine sulfonamide (g » 3.78 mmol)» and tetrahydrofiurylamine (047 mL; 1.7 eq)» (VY) EtOH (mL); and 0 q (¥ ml) the crude product was purified by MPLC 0 and using a mixture of two grains (EtOAc) in a ratio of 1:1 to obtain the title compound in the form of a bright yellow solid (1/634.17 pg) Joos 1 H NMR (400 MHz, CDCl): 5 1.73 - 1.62 (m, 1 H), 1.94-2.13 (m, 3 H), 3.27-3.47 (m, 2 H), 3.80-3.98 (m, 2H), 4.15-4.22 (m, 1 H), 6.51 (s, 1 H), 6.81 (d, J=9.18 Hz, 1 H), 7.35 (dd, J=8.98,2.54 Hz, 1 H), 7.44-7.48 (m, 2 H), 7.55-7.59 (m, 1 H), 7.63 (d, J/=2.73 Hz, 1 H), 7.69-7.72 (m, 2 H), 8.18-8.20 (m, 1 H).Vo Step C: =F] —N amino-4-[[(tetrahydr = ¥—furanyl)methyl]amino]phenyl]btzensulfonamide.

-Yo-— bit : 8 mile following NH 9 - 4 9 a I followed the step e procedures in Example -3» using AN [©-nitro-4-[[(tetrahydro-"-furanyl) methyl[amino]phenyl]btzen sulfonamide VERY (gm) ?mM (de) and a catalytic amount of C/Pd 7011 in (Jo 0+) EtOAc analysis of 10048 indicated that the title 0 compound was High purity (more than 5 708) can be used directly in the following linear 1 H NMR (400 MHz, CDC): 8 1.70-1.61 (m, 2 H), 1.89-1.96 (m, 2 H), 2.01 -2.09(m, 1 H), 2.97-3.02 (m,1 H), 3.12-3.16 (m, 1 H), 3.34-3.59 (m, 3 H), 3.74-3.90 (m, 2 H) , 6.28 (s, 1H), 6.33 (dd, J=8.20, 2.34 Hz, 1 H), 6.44 (d, J=8.40 Hz, 1 H), 6.53 (d, J=2.34 Hz, 1 H), 7.39-7.44 (m, 2 H), 7.50-7.54 (m, 1 H), 7.68-7.72 (m, 2 H).\Example 14 [-1]-<(cyclobutylmethyl) =Y, 0) = Y= dimethylethyl) -151- Ju imidazole -*-yl]-benzenesulfonamide: oH N 8 N 9

M-Step 1-[NT (1,1-cyclobutyl( Y(t-dimethylethyl) THY b-imidazole —0- yl]-benzene-sulfonamide.”er Cenc butyl AS] -4- [amino-©[SN using VY] Followed the procedures of Step A in the example mmol) (for method 3.71 g” VARA)methyl)amino[phenyl]-benzene sulfonamide 0 and chloride Preparation GU DMAP (Jo 40) Refer to next steps b “c” and ©11:01 M eq. ACOH was purified, followed by 4 mL of 111 mL 0.3 (1,3) ilagaloyl This was followed by a 1:1 purification using a mixture of hemicane/M 8:06 at a ratio of MPLC to the crude product by

Chior HzO in NeCN of Yo-9075 using Sal-phase HPLC by lyophilization (YYT,A) TFA (2019). To obtain the title compound in salt form (2019). 0 Y NMR (400 MHz, µm: 5 1.60 (s, 9 H), 1.81-1.93 (m, 2 H), 2.01-2.07 (m, 4 H), 2.78-2.83 (m, 1H) ), 4.55 (d, J=6.44 Hz, 2 H), 7.22 (dd, J=8.98, 1.95 Hz, 1 H), 7.43-7.47 (m, 2H), 7.52-7.56 (m, 1 H), 7.59 (dd, J=1.95, 0.59 Hz, 1 H), 7.70 (dd, J=8.98, 0.59 Hz, 1 H), 7.76-7.79 (m, 2 H); MS (EST) (M+H)- = 398.0.nitrophenyl]-bzene Y=[(cyclobutylmethyl)amino]-4[-N Step B: 0-sulfonamide:

2 -la OH NO, c : © 2 1 BGA _.thin TIL NH 0 2 a 2 0 Followed the procedure for step c in example (VY) using 17-(4-fluoro-?-nitrophenyl = betzine sulfonamide 1 (gr » 73.778 mmol) » and cyclobutylmethylamine (45.17 3 pgY ,1 mcg) » and 8:013 VY mL); oO (© ml). The crude sludge was purified by MPLC© using a mixture of [OLS M8:08: ? Thus, to obtain Marbasc Al-Awan in the form of a solid with a bright orange color (1/.7 μm BGY (TOV): !, H NMR (400 MHz, CDCL): § 1.78-1.73 (m, 2 H), 1.88- 2.00 (m, 2 H), 2.13- 2.21 (m, 2 H), 2.62-2.73 (m, 1H), 3.27-3.30 (m, 2 H), 6.44 (s, 1 H), 6.78 (d , /=9.18 Hz, 1 6 (dd, J=9.08, 2.44 Hz, 1 H), 7.45-7.49 (m, 2 H), 7.55-7.60 (m, 1 H), 7.66 (d, J= 2.73 Hz, 1 H) 7.72-7.74 (m, 2 H), 7.93-7.98 (br s, 1 H).01 Step C:—N [*-amino-4-[(cyclobutylmethyl) ) [tl phenyl] - benzenesulfonamide NO Clad NE said PCL — TCL, NH NH Followed step e procedures in example or using = [4 - [(cyclobutylmethyl)amine] ] 1 -”- Nitrophenyl]-Betzenylsulfonamide MOY, Bham” 7.77 milligrams (gr) and a catalytic amount of

vA .C/Pd in YO (EtOAC mL) with shaking for 48 hours. Lal MS 10 analysis indicated that the title compound was of a sufficient degree of purity (more than 2095) and could be used directly (AY BGY = YT, A) in the next step (product Kz NMR (400) MHz, CDCL): 5 1.78-1.68 (m, 2H), 1.86-1.98 (m, 2H), 208-216 (m, 2

H), 2.54-2.62 (m, 1 H), 3.04 (d, /=7.42 Hz, 2 H), 3.11-3.42 (brs, 2 H), 6.28-331 (br.s, 1©

H), 633 (dd, 728.40, 2.34 Hz, 1 H), 6.43 (d, J=8.40 Hz, 1 H), 6.56 (d, /=2.34 Hz, 1 H), 7.40-7.44 (m, 2 H ), 7.50-7.54 (m, 1 H), 7.69-7.71 (m, 2 H).

He or she | Example \%-1[-N(cyclopropylmethyl)-7-1 1(-diJet ethyl)-151-butyrimidazole -0—yl]-pu sulfonamide 0 N yl 8 ASRS 0 Step A: “-1[(cyclopropylmethyl) Y= (3,0-dimethylethyl) = THY imidazole -©-yl]-benzene sulfonamide Ll For less N m nN NH, bmO __ Poe V 4 8 emit the step a procedures in example VY using AN [©-amino -4-[(cyclopropylmethyl)amino]phenyl] - Betzin-sulfonamide (7771,4) (of 7.77 mmol) (0 method of preparation see steps b “c” CHCLyy (dl (+0 ml); SU DMAP and lingaloyl chloride 1) , + mL” 111 eq) followed by 10 mL of ACOH The crude product was purified by reversed-phase HPLC using 9048-15 of MeCN at 0. The product was lyophilized to obtain On the title compound in the form of salt TFA (+0 pH 204,7).

—-A— m 1 H NMR (400 MHz, CDsOD): § 0.57-0.61 (m, 2 H), 0.65-0.70 (m, 2 H), 1224.25 (m, 1

H), 1.62 (s, 9 H), 4.47 (d, J=6.44 Hz, 2 H), 7.23 (dd, J=9.08, 2.05 Hz, 1 H), 7.43-7.47 (m, 2 H), 7.52 -7.55 (m, 1H), 7.62(d, J=1.95 Hz, 1H), 7.74 (d, J=8.98 Hz, 1H), 7.73 7.78 (m, 2H); MS (ESI) (M+H) - + = 384.0. nitrophenyl]-bazine -*- [il (J) Step B: <- [6-[recyclopropyl 0 sulfonamide. Ola NO,

HH 5 - Asia 1 Al Ra

F “v = fluoro-?-nitrophenyl (-4) IN using VY I followed step c procedures in example

VY cdr 1, 4 (gr » 3,78 mmol) » cyclopropylmethylamine 1) betzine sulfonamide

MPLC (ml)” and water (0 ml). The crude product was purified by EIOH equivalent (VY) at 0? on a layer of silica gel to obtain 1:1 using a mixture of hexane/M 8:08 (TOV) with AYA, TY acid on the title compound in the form of a bright orange solid 1 11 NMR (400 MHz, CDCl) : § 0.92 0.33 (m, 2 H), 0.63-0.67 (m, 2 H), 1.14-1.19 (m, 1

H), 3.13 (dd, J=7.03, 4.88 Hz, 2 H), 6.42 (s, 1 H), 6.76 (d, /=9.37 Hz, 1 H), 7.36 (dd,

J=9.18, 2.54 Hz, 1 H), 7.45-7.49 (m, 2 H), 7.56-7.59 (m, 1 H), 7.67 (d, J=2.54 Hz, 1 H), 0 7.71-7.74 (m , 2 H), 8.07-8.13 (m, 1 H).

2-L(/- . Step C: <- ]= Amino-4-[(cyclopropylmethyl)amitab]] phenyl]-bazine sulfonamide.: NO Cg N NH Ryl Poo Me NH 9 Bit The procedures for step e were followed in the oF example using “—N[4-[(cyclopropylmethyl)amino] and -©-nitrophenyl]-benzene-sulfonamide (877.7 pH 7.708 mmol)” and a catalyst amount of 000 In (To) EtAc mL) the 10/148 analysis indicated that the title compound was of sufficient purity (ST of 7095) and could be used directly in the next step. yield = 54 L by 70,000 1 H NMR (400 MHz, CDCl): § 0.20-0.24 (m, 2 H), 0.53-0.58 (m, 2 H), 1.08-1.12 (m, 1 H) ), 2.87 (d,/~7.03 Hz, 2 H), 3.28-3.48 (br.s., 2 H), 627-631 (br.s., 1 H), 631-634 (m, 0 H), 639-641 (m, 1H), 6.57 (d, J=2.34 Hz, 1 H), 7.40-7.44 (m, 2 H), 7.49-7.54 (m, 1 1 H), -7.69 7.71 (m, 2 H). Example YY —t -" [-<butyl -1-(tetrahydro—HY—pran-4-ylmenell) fm —HY— 0 imidazole [O yl] “N= miguel benzene sulfonamide.

=AY~- 0 0 i /

OFng.

N : 0 step NT]¥— + -butyl -1-(tetrahydro-157-pyran-4-yl (J = 1-benzimidazole =0-yl] -<-methylbenzenesulfonamide. 0 an |!0 !a a b 01 a b 0 0 The procedure for step eg tel-i was followed using 1}-N-amino-sc [(tetrahetero-7-pyran-4-ylmethyl)amino] N= {Jed methyl betzine sulfonamide (1.8 mg GYR mmol) (for method of preparation see next steps b “c”) and trimethyl acetyl chloride 1.0 ml TAY 1715 mm ( pr and 0348 (0 pH 1.058 mmol) in ?mL of DCM The second step was carried out in ?mL of glacial acetic acid. The final product was purified by reversed-phase HPLC using + = 70/0 of a mixture of [CHCN] water and then lyophilize this product to obtain the title compound in the form of the corresponding TFA salt. ): 6 1.55 (m, 2H), 1.60 (m, 2H), 1.68 ) 9H), 2.37 (m, 1H), 3.27 (s, 3H), 3.36 (ddd, J= 11.57, 2.64Hz, 2H), 3.93 (d, J=3.52Hz, 1H), 3.96

—AY- as (m, 1H), 4.53 (d, J=7.42Hz, 2H), 7.31 (dd, J = 8.98, 1.95Hz, 1H), 7.54 (m, SH), 7.68 (m, 1H), 7.89 (d, J = 8.98Hz, 1H); MS (ESI) (M+H)+442.3. yl m = pyran —HY = nitro -4-[tetrahydr = } —N— methyl —N Step B: sulfonamide. ojo (methyl)amino]phenyl)

OF TRAH HL 1 NO, © — 1 : F fi ia: 6 The procedures for Step C were followed in Example “1” using 17-(4-Fluoro-7-nitrophenyl) “N=methylbenzenesulfonamide of 001 (777 mmol) (for method of preparation see Hazard B”C in (FJ, 4-aminomethyltetrahydropyrane) (£0 g; FAT + mmol (Vr) TEA + ml EAT 5+ mmol) in ? mL of LEOH the residue 0 was dissolved in 8086 and washed J gles 00180 , 9065 and a saturated solution of sodium bicarbonate; and pyrene” and then dried that substance by anhydrous sodium sulfate. Crude eb was also purified by flash chromatography on a silica gel bed and using a linear regression of 4 .709 with a value of VYY = -30. 705 Product EtOAc Hexane/'H NMR NMR (400 MHz, CHLOROFORM-D): 5 1.44 (m, 2H), 1.74 (m, 1H), 1.77 (m, 1E), 1.96 (m, 1H), 3.13 (s, 3H), 3.23 (dd, J=6.74, 5.57Hz, 2H), 3.43 (ddd, J=11.81,2.15, 0 2H), 4.40 (dd, J =11.13,3.91Hz, 2H), 6.84 (d, J = 9.18Hz, 1H), 7.49 (m, 3H), 7.61 (m, 3H), 8.21 (m, 1H).

-At- =

Step C: =F} —N amino -- [zetrahydr-157-pyran-4-ylmethyl)amibo]

Jet —N— {Jd benzenesulfonamide

NG 7 |

The procedures for step e were followed in Example = oF using 17-mF} N= te nitro-)-0 [(tetrahydro-1173-pyran-4-ylmethyl)amino]phenyl)butylsulfonamide (1178 pH)

, = yield EtOAc in mL of 01 in 60070101 mmol)” and a catalyst amount of +, YR)

MS (ESD) (M+H)-376.16. .7054 Ai

Example YY z

—N[-2-butyl-1-(tetrahydro)—HY—pyran-?-yl (Jd-171-br

0 imidazole —o— yl] -<- methylbenzene sulfonamide. 97 OF rg N 2 6 Step A: —N [7- : -butyl -1- (tetrahydro-117-pyran - ?-ylmenel) - —H) Benz imidazole =0—yl]-<-methylbenzenesulfonamide.

—Ao- 2 ata 5 or — ai” ia N Followed the procedures for step e in Example-4; using oF}AN amino-4-[(tetrahydro-7pyranYomethyl)amino]phenyl)-18-methylbenzene sulfonamide 410 BGSATO mmol) (for method of preparation see Steps B” c next” and trichloride (de 0 acetic ATA co vy) + mmol)” (Y)DMAP b sr YO mmol) in ? ml of 0014. The second step was performed in ? mL of glacial acetic acid; The final product was then purified by reverse-phase HPLC using Yo = 90850 from a mixture of CHRON / 31.0 and then lyophilized to obtain the title compound in the form of salt BU TFA Product = YY in Ham ( YEA) 'H NMR (400 MHz, METHANOL-Ds): 5 1.50 (m, 2H), 1.58 (m, 3H), 1.67 (s, 9H), 188 \ » (m, 1H), 1.91 (m , 1H), 3.22 (ddd, J= 1147, 2.64Hz, 1H), 3.27 (s, 3H), 3.85 (m, 2H), 4.65 (m, 2H), 7.29 (dd, J =9.08,2.05Hz, 1H), 7.51 (d, J = 1.56 Hz, 1H), 7.54 (m, 3H), 7.68 (m, 1H), 7.87 (d, J = 8.98Hz, 1H), MS (ESI) (M+H) += 442.3. Anal. Calcd for

C24H31N303S8+1.5 TFA +0.1 H20: C, 52.78; H, 5.36; N, 6.84. Found: C, 52.83; H, 5.37,

N, 6.90. Vo Step B:—N-methylsg vy}nitro-4-[(tetrahydro-117-pyran == ylmethyl)amino]phenyl)butylsulfonamide

z OH. aS TH CT — OT F op i 0 The procedures for step c were followed in example of using 17-(4-fluoro-7-nitrophenyl) “N=methylbenzenesulfonamide (00 mg”) VT + mmol)” and 7-Aminomethyl tetrahydro Olt chloride (30 pg 1147 mm “(Jar, 18 (0, 18 ml, 407 mmol) in © © ml from 8:011 . The residue was dissolved in BIOAC and then washed with 765 (KHSO, then a saturated solution of sodium bicarbonate and pyrene) and dried by anhydrous magnesium SxS. The crude product was purified by flash chromatography on a gel bed. silica using DCM first and then using LU EtOAc as an equilibrium product = 8HBH (JOA) 'H NMR (400 MHz, CHLOROFORM-D): 5 1.46 (m, 1H), 1.55 (d, J = 7.03Hz, 2H), 1.60 0 (m, 2H), 1.67 (m, 1H), 1.91 (m, 1H), 3.13 (s, 3H), 3.29 (m, 1H), 3.37 (m, 1H), 3.50 (ddd, J =11.33,2.93Hz, 1H), 3.62 (m, 1H), 4.06 (m, 1H), 6.83 (d, J = 9.37Hz, 1H), 7.46 (dd, J =9.37,2.54Hz, 1H), 7.50 (m, 2H), 7.57 (m, 2H), 7.61 (m, 1H), 8.33 (m, 1H). Step C:—N (©- Amino-6-[zetrahydro—HY=pyran-7-ylmethyl)amino] vo-phenyl)N=methylbutynsulfonamide.

0 no ( - 0 | 77 Oper OH Sa NH, CL — YT NH CY H bid You followed the procedures for step e in the oF example using 17-methyl N= }55-7 -? - [(tetrahydro-143-pyran-7-ylmethyl)amino]phenyl)benzene sulfonamide (00) Bghi 1776 mM (J pr) and a catalytic amount of 00090101 in Vo mL of EtOAc was produced. = 497 pH m MS (ESI) (M+H):376.17.(Y04Y) Ex. YY [-1[(cyclohexylmethyl)2-1(hydroxy J 0 egyl) THY Benzimidazole —0— yl]-benzene sulfonamide 3H HN Tr 5 L between N 5 0 diisopropylethylamine (8 YAN, pH 7.75 mmol) was added to Solution –—Y}oN amino-4-[(cyclohexylmethyl)amino]phenyl)ptyrene sulfonamide (5.40.1 Bg 0.00 mmol) (For method of preparation see steps B, C, D in example (VY and ?-hydroxyisobutyric acid (171.8 pH 1.66 mmol) at 0145 (Je 01) was heated to 0° C with stirring for 71 minutes. HATU (4, 104 pH (0.80 mmol) and done

ATA is alive.. The reaction mixture is stirred for an hour, YE, at room temperature; The mixture was then diluted with water (100 (Js) and extracted by M8:08 0 XY © mL). Then the accumulated organic phases were washed using sodium chloride (Jo 71) and dried with anhydrous sodium sulfate. After filtration and concentration, the residue was dissolved in acetic acid (0 ml) Js 0 sealed tube. The solutions were heated below Nem C using a Personal Chemistry Smith Synthesizer microwave for 00 minutes. Upon evaporation and removal of the solvent, the residue was diluted with 06:8 (+V+ml); The material was then washed with sodium midar oxide (IN 01 ml)” and a irradiating solution of sodium chloride (XY 01 ml)” and dried with anhydrous sodium sulphate. After filtration, the remaining substance 0 was purified by MPLC (EtOAC) on a layer of silica gel) to obtain 34.76 pH (76517) of the title compound in the form of a white solid.

TFA salt 'H NMR 400 MHz, CDsOD): 31.17 (m, 5 H), 1.56 (m, 2 H), 170 (m, 3 H), 176 (s, 6

H), 2.09 (m, 1 H), 4.48 (d, J=7.62 Hz, 2 H), 7.23 (m, 1 H), 7.47 (m, 2 H), 7.56 (m, 2 H), 7.72 ( d, J=8.98 Hz, 1H), 7.79 (m, 2H); MS (ESI) (M+H)+= 428.0; Anal. Calcd for 0

C23H29N3038+1.2TFA: C, 54.05; H, 5.39; N, 7.45. Found: C, 54.09; H, 5.50; N, 7.42.

YE Example J (HY = methyl ethyl) -1- mechphoxi (1-(fei)(cyclohexyl-1[-<imidazole —0— yl] —N— methyl.benzene sulfonamide .

oo. . 2 0 z a ~ N

Sodium hydride (TY) in VA mmol) was added to the glucose of 7<--1[(cyclhexylmethyl)-7--1(hydroxy-1-methyl) =H = (Jd petyrimidazole om yl] - benzene sulfonamide YT ot (111, + mmol) (for method of preparation see (YT Je) in (BV) THR under Sho C with stirring for 91 148 methyl iodide (4,148 mg” 017 mmol) was added and the reaction mixture was stirred again for 4 hours at room temperature, then the mixture was quenched with a saturated solution of sodium bicarbonate (3 ml); The mixture was then extracted with EtOAc (0 XY) 5 ml.The combined organic phases were washed with NaCl (V0 ml) and dried with anhydrous sodium sulfate. After filtration and concentration, the residue was purified using MPLC (Mexane/EtOAc at a ratio of 1:1 on a bed of silica gel) to yield 1,1,9 pH (7097) of the title compound in the form of a colorless syrup. » And part of it was converted to TRA salt in the form of a solid

White. (m, 5 H), 1.62 (m, 2 H), 1.70 (m, 1 H), 1.76 (m, 2 1.21 E' H NMR (400 MHz, CD,0D): H), 1.79 (s, 6 H), 2.13 (m, 1H), 3.27(s,3H),3.31 (5, 3H), 4.46 (d, 7.62 Hz, 2H), 0 (m, 1 H), 7.47 (m, 1 H), 7.55 (m, 4 H), 7.67 (m, 1 H), 7.76 (m, 1 H) ; MS (ESD 7.24 (M+H) = 456.0, Anal.

Caled for C,H,N,0,8+0.8TFA+0.6HLO: C, 57.29; H, 6.33; N, Found: C, 57.34; H, 6.31; N, 7.33. .7.54

-q.= 2 mal Yo -1[(cyclohexylmenyl) -7- -1-(meshoxi-1-methylethyl) FHV imidazole —0—yl]-pebenzene Sulfonamide. QUIT PUK 0

e I followed the same procedure as § using sodium hydride (EC) in 017 mmol neighborhood T[-1](miclarhexylmethyl)-1(SY -1-methylethyl oxyhydride) = THY petyrimidazole [mom = benzene sulfonamide (AGT) pH” 1.71 mmol) (for method of preparation see example (VY) and methyl iodide (8 YV, 0.19 mmol) in 01( THE ML). The title compound was purified by MPLC (hexane/EtOAc in a ratio of 1:1 on 0 bed of silica gel) to yield 4,8? Beef (OFA) from Oy flag syrup

Part of it has been converted into a TFA salt in the form of a white solid. 1 (m, 5 H), 1.59 (m, 2 H), 1.68 (m, 1 H), 1.74 (m, 2 1.18 E H NMR (400 MHz, CD,0D): H), 1.78 (s, 6 H), 2.09 (m, 1 H), 3.30 (s, 3 H), 4.42 (d, 17.42 Hz, 2 H), 7.23 (dd, J=9.08, Hz, 1 H) , 7.47 (m, 2 H), 7.55 (m, 1 H), 7.58 (d, J=2.15 Hz, 1 H), 7.72 (d, J=9.18 Hz, 2.05 (m 2 H), MS ESD) (MH) = 4420; Anal.

Caled for 0 780 © 1 C,,H,,N,0,5+0.9TFA+0.5H,0: C, 56.01; H, 5.99; N, 7.60. Found: C, 55.97; H, 6.00; N, .7.47

-41- 1

SY Example J -butyl-1-(cyclohexylmethyl) = H = bisimidazole —0— yl] —V-N - dimethyl = “HY imidazole —€—sulfonamide. No A OK TH H 0 0 e I followed the procedures of step a in the example of using ?- + - butyl (JS) N= hemexyl N= (J methyl -131-ju imidazole amine (40 mg 10174 mmol); and 1-methyl-111-imidazole-4-sulfonylchloride (VEE TY) mmol) in ? 4 mL of Go containing a catalytic amount of DMAP, the solvent was evaporated and the purification of the mixture was carried out by reverse-phase HPLC using (HO 701:07 90/850 = 71) and then lyophilized 0 to obtain the title compound. in the form of the corresponding TFA salt. H), 1.67 (s, 1 H), 1.75 (m, 2H), 2.08 (m, 1H), 3.30 ( 3 H), 3.73 ( 3 H), 4.43 (d, J=7.62 Hz, 2

H), 7.44 (dd, J=8.98, 2.15 Hz, 1 H), 7.60 (d, J=1.37 Hz, 1 H), 7.65 (d, J=1.56 Hz, 1 H), 7.74 (4, 1- 098 Hz, 1H), 7.82 (d, J=8.59 Hz, 1H); MS (ESI) (M+H) 510 444.0; Anal.

Caled for C,H, .N.O,S + 2.0 TFA +0.1H,0:C, 48.15; H, 527; N, 10.40. Found: C, 10 48.06; H, 5.21; N, 10.55. ‎YYJ

aye : <- (8-,7[[1-:-butyl-1-(cyclohexylmethyl) = HY-benzimidazole-0yl](J)amino]sulfonyl) -4-methyl-6,1-thiazole-?-yl)acetamide: Xen pmp N H 0 0 0 Followed the same procedure as step a in example ct using ?- + -butyl (AS) -1 - © hexylmethyl) “N= methyl-151-Ju imidazole -#-amine (40 pH ATE mmol); and 7-acetamido-4-methyl-#-thiazolesulfonyl chloride (44 mg WWE mmol) in 7 mL of DCM containing a catalyst amount of DMAP the solvent was evaporated and the residue was then purified by HPLC Ju Sell phase using YA = 31 10/07 and then lyophilized to obtain the title compound in the form of the corresponding 0 TFA salt (product = 1 H mg (Fore (m, 6 H) , 1.59 (m, 2 H), 1.65 (m, 11 H), 121 h NMR 400 MHz, METHANOL-D: yz (m, 4 H), 2.16 (s, 3 H), 3.32 (s, 3 H), 4.44 (d, }=7.81 Hz, 2 H), 7.41 (dd, J=9.08, 2.08 Hz, 1 H), 7.66 (4, 12176 Hz, 1 H), 7.86 ( d, J=8.98 Hz, 1 H); MS (ESD) (M+H) 2.05 Anal.

Caled for C,H,N,0,S,+1.6 TFA + 0.4 HO: C, 47.88; H, 5.33; N, 9.90. ;518.0;Found: C, 47.88; H, 5.28; N, 10.02. \o Example YA

. M4 eT]-“#-butyl-1-(cyclohexylmethyl)-1579-bazimidazole =0—yl] N=menylpipyridine -*-sulfonamide: Co 0:2 N mil B ELA — 2 0 I followed the same procedure as Step A in Example -4, using ?- ? -butyl-1-(cycl 0hexylmethyl)-28-methyl-151-ju imidazole momamine (10 1717 mM “(rr) Ty pyridine sulfonyl chloride hydrochloride (0 g) » 775 mmol) in ?ml of 4 containing a catalytic amount of DMAP, the solvent was evaporated and the product was purified by reversed-phase HPLC using (HO / CHRON 70/80 - 701) and then Cay orl a Freeze-drying process to obtain the title compound in salt form BUI TFA (product = 0 mMg (JUV 1 H) NMR (400 MHz, METHANOL-D,): 5 1.23 (m, 5 H) , 1.62 (m, 2 H), 1.66 (s, 9 H), (m, 1H), 1.76 (m, 2 H), 2.09 (m, 1 H), 3.315, 3 H), 4.45 (d , J=7.62 Hz, 2 H), 7.32 1.69 (dd, J=8.98, 2.15 Hz, 1 H), 7.58 (d, J=1.56 Hz, 1 H), 7.61 (dd, J=8.01, 4.88 Hz, 1 H), (d, J=8.98 Hz, 1 H), 8.02 (dt, J=8.15, 1.88 Hz, 1 H), 8.59 (s, 1 H), 8.81 (s, 1 H) ; MS 7.87 0 17 :449.63 : 0.3 0.5 +174 2.0 + 05 (ESD) (MH) 441.0; Anal.

Caled for C, H, N, 8.27. Found: C, 49.69: H, 5.20; N, 8.29.: 5.21 Example 49?:

-86- > - imidazole -#-yl] ju -159- (cyclohexylmethyl) -1-butyl -t—Y] -< and 1-trimethyl-119-imidazole —0—sulfonamide .VN A 0

HN N satisfied x

Td — or

N \ .

JS (cyclo-1- followed the same procedure as Step A in Example 4 using ?-2-butyl wa" eds 1174 mM imidazole —0—amine)£0 Ag-1311-myl “N-methyl)© mmol) in ?ml of 1700 pH TA imidazole-H-sulfonyl chloride Jie dy- = the solvent was evaporated” and then DMAP purified the contents On a catalyst quantity of 4 9 “H,0 / 0 76 vv — Ya (using Sal) phase HPLC by No - corresponding (product C) TFA lyophilization was carried out to obtain a compound Address in salt form 08 0 Baham 1 01 11 NMR (400 MHz, METHANOL-D,): ?1.25 (m, 5 H), 1.64 (m, 2 H), 1.69 (s, 10 H), 1.78 (m, 2 H), 2.11 (m, 1 H), 2.59 (s, 3 H), 3.40 (s, 3 H), 3.49 (s, 3 H), 4.48 (d, J=7.62

Hz, 2 H), 7.53 (dd, J=8.98, 1.95 Hz, 1 H), 7.78 (d, J=1.95 Hz, 1 H), 7.92 (s, 1 H), 7.95 (d,

J=8.98 Hz, 1H); MS (ESI) (M+H) 510 458.3; Anal. Calcd for C,,H,,N,O,S +3.0 TFA +0.9 HO: C, 44.16; H, 4.92; N, 8.58. Found: C, 44.24; H, 5.00; N, 8.43. \o > . y 0 is an example

—-q0— 0 - [?-, -butyl - 1 - (tetrahydro –HY—pyran -4-ylmenheyl) = HY secret imidazole 0—yl] 10 N= = Tri —HY = Jt epimidazole —0—sulfonamide. 7 . Jags 8 HN © > TA A 0 Step A: “- ]= 0-butyl-1-zetrahydro-157-pyran == yl (Jie -© 0c1-bizimidazole) 0— yl] 00 N = ?- trimethyl = HY imidazole —0— sulfonamide 0 | ? + 8 mL] 8 AN 5 A N stirred ?- + - butyl N=methyl-1- (tetrahydro = 117-pyran-4-ylmethyl)-=H) petyrimidazole-e-amine (for method of preparation see LS Pt b c) d m EY) 0 pH R mL Vy “(J se ?- Di Jen imidazole -0-— Sulfonyluyl Chloride YY) bVY + mL (ge) in an amount of ? ml of DCM containing a catalyst amount of DMAP and this was stirred at room temperature overnight. The solvent was evaporated and the product was purified by reversed phase HPLC using FO 9070 = 01 (CHRON) then dried. product by lyophilization to obtain the title compound in the form of TFA salt BL 0 (for product = TE by (JOA)

-9 “= ym 1 H NMR (400 MHz, METHANOL-D,): § 1.50 - 1.56 (m, 2 H), 1.57 - 1.64 ),2 H), 1.68 (s, 9 H), 2.32 -2.41(m, 1 H), 2.58 ) 3 H), 3.33 (dt, J= 11.42, 2.34 Hz, 2 H), 3.38 (5, 3

H), 3.49 (s, 3 H), 3.90 - 3.93 (m, 1 H), 3.95 (d, J=2.54 Hz, 1 H), 4.54 (d, J=7.62 Hz, 2 H), 7.52 (dd , J=8.98, 2.15 Hz, 1 H), 7.76 (d, J=1.56 Hz, 1 H), 7.89 (s, 1 H), 7.96 (d, 18

Hz, 1H); MS (ESI) (M+H) 460.0; Anal. Calcd for C,,H,,N,O,S+2.1 TFA+23H,0: ©

C, 44.12; H, 5.40; N, 9.72. Found: C, 43.89; H, 5.02; N, 10.12 pyran-4 — ylmethyl)amino] —HY— Step B: methyl[©-tetro —6— [(tetrahydrophenyl)carbamate 1 MN 2 2 8 NC, high CI hd 2 0 3 TI Sitt NH

F

OQ

and 4- (a gram” 9.77 m¥V) methyl (4-fluoro-?-nitrophenyl) carbamate 0 mL mSn 50 mmol) was stirred in an amount of 1117 g » NYA) aminomethyl tetrahydropyrane 6/8 m for a period of Vo at a temperature of (pr mM VE (Jo Y) TEA containing 3

Yoo and washed with EtOAc for 1 hour. The solvent has been evaporated, and then the material has been harmed to remain in

GS bitter saline; saturated aqueous J sls of sodium bicarbonate”; aqueous J sls; KHSO, thereafter with anhydrous magnesium sulfate. The product was purified by Codd \ o 1:1 ratio EtOAc flash chromatography on a silica gel bed using hexane/TOMA cpl = 57 as the separator (for product).

: and 1

H NMR (400 MHz, CHLOROFORM-D): 5 1.42 (ddd, J=25.24, 12.06, 4.49 Hz, 2 H), 1.73 (d, J=1.76 Hz, 1 H), 1.76 (4, J=1.95 Hz , 1 H), 1.88 - 2.01 (m, 1 H), 3.22 (dd,

J=6.74, 5.57 Hz, 2 H), 3.42 (td, J=11.86, 2.05 Hz, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d , /=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03 - 8.09 (m, 2 80 o pyran == yl-methyl)amibo] —HY amino ~= [zetrahydro =F} Step C: methylphenyl)carbamate. 1 8 i - y NH, roy — atmosphere © NH 35 NH [9 oo {d= pyran-4-ylmethyl)amino] —HY= methyl (©-nitro-4-) dissolved [(tetrahydrocontaining an amount of BtOAC party in ml of 0 5 mmol) in AVA g” Yio) carbamate ye The solution was shaken in a medium of hydrogen under a pressure of 6 psi CPA 90101 from Overnight at parr in. using a gram hydrogenation apparatus; 3.78 ply = solvent evaporation (Celite chamber). 'H NMR (400 MHz, CHLOROFORM-D): 5 1.40 (ddd, J=25.09, 12.01, 449 Hz 2H), 0 1.70 - 1.74 (m, 1 H), 1.74 - 1.77 (m, 1 H), 1.81 - 1.92 (m, 1 H), 2.99 (d, J=6.64 Hz, 2 H), 3.34 (brs, 2 H), 3.41 (dt, J=11381, 2.15 Hz, 2 H), 3.74 (s, 3 H), 3.99 (d, J=3.51 Hz, 1H),

> Ham (br.s, 1 H). Step D: methyl[?- +-butyl-1-(tetrahydro-57-Ol-4-ylmethyl)-ju-131imidazole-# - il carbamates. ak NH, Log | a a EERE of "0 grown solute Ji (7-amino-4-[zetetrahydro-BY-pyran-4-ylmethyl)Lidphenyl(carbamate) 3 7.7 AY cpl mVTE pr oY) DMAP (dpe mmol) in yo mL DOM trimethylacetyl chloride (1.01 mL; 7 mmol) was added in the form of drops” and the solution was stirred under room temperature for 0 h. Then it was washed with a saturated aqueous solution of sodium bicarbonate and then with concentrated saline and dried with anhydrous magnesium sulfate. The residue was also dissolved in yo 80011 ml with Heating below 1171°C for one hour using a microwave device of the type of Personal Chemistry, the solvent was evaporated, then the residue was dissolved in EtOAc, and then washed with a saturated aqueous solution of sodium bicarbonate and pyrene; then dried with Ve magnesium sulfate Anhydrous The crude product was also purified by flash chromatography on a silica gel bed using 4: ¥ hexane/acetone as the eluting. (Product = (Jot pl 81 qq.

H NMR (400 MHz, CHLOROFORM-D): 1.48 - 1.54 (m, 4H) 1.56 (s, 9 H) 2.23 - 2.35 (m, 1 H)3.27-3.35(m, 2H) 3.78 (5, 3 H) 3.96 (t, J=2.93 Hz, 1 H) 3.99 (t, /=3.03

Hz, 1 H) 4.18 (d, J~7.42Hz, 2H) 6.63 (br.s, 1 H) 7.24 - 7.28 (m, 1 H) 7.41 (brs, 1 H) 7.61 (d, /=1.95 Hz, 1H). © Step E: ?- –t butyl –N—methyl -1-(tetrahydro—HY—pyran-;-ylmethyl) -151-ju imidazole —0—amine: z C0 with compass N : 8 0 oy or dissolved methyl t=]-butyl-1-)18hydro ~HY= pyran-4-yl (sr -111 - Butyrimidazole -*-yl]carbamate (VA) g) 5.71 mmol) in an amount of Vo ml VY 4 ml 1/,7) ether [AMY 11061 under 0 degrees C. Drops of THF were added from 0 minutes. An amount of Vo m was added slowly for a period of Tho mmol) and the solution was stirred below 1 degree with the mixture being stirred again under LIATHG with baking soda (1.1 mmol) of GAA at room temperature over the night. The reaction mixture was quenched below zero degrees C by adding 01 followed by adding water while stirring the solution at room temperature for (Jo ©) MeOH 0 min. Then anhydrous 1182504 01 (g) was added and the solution was stirred at room temperature for another 30 minutes. The solution was also filtered, then the solvent was evaporated, and the remaining substance was then dissolved in C 28:08, then washed with an aqueous solution of sodium bicarbonate and pyrene. And follow a. This is a process of drying by anhydrous magnesium sulfate and the solvent was evaporated. Product = (Joa A in grams; 4 1

H NMR (400 MHz, CHLOROFORM-D): § 1.49 - 1.53 (m, 4 H), 1.53 - 1.57 (m, 9 H), 2.22 - 2.32 (m, 1 H), 2.87 (s, 3 H), 3.26 - 3.35 (m, 2 H), 3.95 (t, /=3.03 Hz, 1 H), 3.97 - 4.00 (m, 1H), 4.13 (d, /=7.42 Hz, 2 H), 6.61 (dd, J =8.59, 2.15 Hz, 1 H), 6.99 (d, J<1.95©)

Hz, 1 H), 7.11 (d, /=8.59 Hz, 1 H). Example PY enyl-4-oY]-butyl-01-(19hydro-157-pyran-4-ylmenhesil) -ju 31 imidazole —0—yl[yl](amino]sulfonyl)- oF 5 - dimenyl = “HY 0 pyrrole -?- carboxylate : 2 RK 11 ele A x EN Y 0 M CTO 0 I followed the same procedure as step a in the oF example using ?- + - butyl N= miel -1- 3 | Hydro-——HY (pyran-4-ylmethyl)-111-ptZimidazole = 0—amine (EY) with 4 mM “(dye and ethyl ¢-”chlorosulfonyl)-? 0-Dimethyl-111-pyrrole-No?-carb oxylate (VY oF EE) mmol) in 7 mL of 0034 containing a catalytic amount of DMAP. The product was purified by HPLC with Reversed phase with 01 -

-111- 0 from .013:017 / 11:0 Then the product was lyophilized to obtain the title compound in %v. JOA = 41 mg (for BLU TFA product salt form 1

H NMR (400 MHz, METHANOL-D)): § 1.33 (t, J=7.13 Hz, 3 H), 1.45 - 1.53 (m, 2 H), 1.53 - 1.65 (m, 2 H), 1.68 (s, 9 H), 2.04 (s, 3 H), 2.16 ( 3 H), 2.32 - 2.41 (m, 1 H), 3.24 (s, 3 H), 3.35 (td, J=11.77, 2.05 Hz, 2 H) , 3.93 (d, J=3.51 Hz, 1 H), 3.96 (d, }=3.51 Hz, 1 m H), 4.28 (q, 17.09 Hz, 2 H), 4.54 (d, = 7.62 Hz, 2 H), 7.42 (dd, J=9.08, 2.05 Hz, 1 H), 7.65 (d, J=1.56 Hz, 1 H), 7.91 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H) 531.2; Anal. Calcd for Alu Yamina 05 + 1.4 TFA + 0.6 H,0: C, 51.05; H, 5.84; N, 7.99. Found: C, 51.07; H, 5.91; N, 7.88.

MY Mal 0 Bz HV (tetrahydro-?15-pyrate-4-ylmenyl)-1-butyl-te-7[-<imidazole-0-yl]-4-(hydr Oxymethyl)-<- methylbetzine sulfonamide

HN N HO © M BG OH \ § A 0 y hb 2 83 - (tetrahydrofer - 117 - pyran -4 - ylmethyl) -1- methyl N= stirred ?- - butyl mmol) and 4-formylbutyrenesulfonyl IVT (Bham) To) bisimidazole -*-amine 151-1 containing an amount of DOM (mmol) in an amount of ? ml of 1749 of YA) aqueous chloride Jos at room temperature for two hours. The DMAP catalyst solution was washed out

-101- . of sodium bicarbonate and pyrene” and then dried by anhydrous magnesium sulfate with evaporation of the solvent. The residue was dissolved in (Je 0) MeOH to which (Y +) NaCNBH; gm TAA + mmol) was added. The solution was also stirred overnight at room temperature, then the melt was evaporated and the residue was dissolved in 28016 and washed with a solution of Sb of 0 sodium bicarbonate with concentrated saline; Then it was dried using anhydrous magnesium sulfate with evaporation of the solvent. The crude product was further purified by flash chromatography on a layer (JOYA mull = 00) as an EtOAc eluting material from silica gel using NMR (400 MHz, METHANOL-D,) (TFA salt): § 1.50 - 1.56 (m, 2 H), 1.57 - 1.65 (m, 2 H), 168(s, 9H), 231-241 (m, 1 H), 3.26 (5, 3 H), 3.35 (td, J = 11.57, 2.64 Hz, 2

H), 3.93 (d,J=3.32 Hz, 1 H), 3.96 (d, 123.71 Hz, 1 H), 4.52 (d, J=7.42 Hz, 2 H), 4.68 (s, 2 0 H), 7.30 (dd, 28.98, 2.15 Hz, 1 H), 7.50 (s, 4 H), 7.54 (d, J=1.56 Hz, 1 H), 7.87 (d,

J=8.98 Hz, 1H); MS (ESI) (MH) 472.0; Anal. Calcd for C,;H,;N,O,S +15 TFA +0.3

H 5 10,0: © 51.89; H, 5.46; N, 6.48. Found: C, 51.94; H, 5.48; N, 631. Ex. PY 1 ch - ——t—=Y] butyl -1-(tetrahydr—HY—pyran —€— ylmethyl) = Jet —HY imidazole - -H - yl] —N— methyl —¢— =F 7 3 —HY) triazole (-1-yl menhell) op sulfonamide.

. KN. pg ua . 0 8 c OH b has Pe Ne! .Py) 15-[?- +-butyl-1-(1,5hydro-117-pyran-4-ylmethyl)-111-butylimidazole-e-yl]-4 was dissolved. (hydr and xmethyl) “N=methyl betzine sulfonamide (00 BG 1117 mmol)”; 1.0 YO (TEA ml) VT mmol) in a volume of 0 ml aged 0 00 below zero. Drops of methanesulfonyl chloride (1, RD (6 mmol)) were added while the solution was stirred at room temperature for ? hours. After that, the solution was washed with an aqueous solution of sodium bicarbonate and pyrene, and then dried with anhydrous magnesium sulfate; with vaporization of the tail. The residue was dissolved in ¥ mL of DMF nor 1 (11117 mM BaH (dae) followed by the addition of oY od SHY = triazole VT mm LTTE mol). The solution was stirred at 80 °C for one hour. Then the solvent was removed by evaporation. The product was then purified by Sad-phase HPLC) using CHSCN 9070 - 0/0pq and the product was lyophilized to yield the title compound in the form of BULL TFA salt (product = Yo Bg 32047). 'H NMR (400 MHz, METHANOL-D,): § 1.50 - 1.56 (m, 2 H), 1.56 - 1.65 (m, 2 H), 1.68 (s, 9 H), 2.32 - 2.40 (m , 1H),3.26(s, 3 H), 3.35 (td, J=11.57, 2.64 Hz, 2H), 3.93 (d, 0 J=3.32 Hz, 1 H), 3.96(d,J=3.51 Hz , 1 H), 4.52 (d, J=7.42 Hz, 2 H), 5.74 (s, 2 1 (dd, J=8.98, 1.95 Hz, 1 H), 7.41 (d, J=8.59 Hz, 2 H), 7.54 (s, 1 H), 7.55 - 7.57 (m, 2 H), (s, 1 H), 7.88 (d, J=8.98 Hz, 1H), 8.09 (s, 1 H); MS (ESI) (M+H) 523.0; Anal.779

-112- -

Caled for C,H,N.O,S + 2.4 TFA: C, 47.96; H, 4.61; N, 10.55. Found: © 48.02; H, 4.72; N, 1022. : 6 Ex. (tetrahydro-157-pyran-4-ylmethyl)-1571-paz-1-butyl--?[-< cit Ji ~N= imidazole -# -yl]-4-([(?-hydroxyethyl)amino]methyl) © : sulfonamide. 1 HO 1

HM MN NE 9 a 0 2 8; Stirred ?- + -butyl =N=methyl -1-(tetrahydro—HY=pyran-4-yl (er - -31b-imidazole =0—amine 0A) (VAY mmol) and 4-normyl ptyrenesulfonyl 0 chloride (EY) pH 17710 mmol) in 0 mL of DOM containing a catalytic amount of DMAP at room temperature for approx. ? hours. The solution was washed with a saturated aqueous solution of sodium bicarbonate and pyrene “5 Als” by anhydrous magnesium sulfate. The solvent was then evaporated. The residue was dissolved in MeOH (© ml) containing a few drops of ACOH and sieves partial with an angstrom. Ethanolamine 0.0 7/0 0.0 mL (410 mmol) was added and the solution was stirred under room temperature for 30 minutes. NaCNBH (YT; 1.0 mmol) was added and the solution was stirred under ambient temperature.

1-0 o then washed with EtOAc for hours. The solvent was evaporated, and the remaining material was dissolved in an aqueous chamber veal of sodium bicarbonate and saline 5, and then dried by los. Reverse phase HPLC anhydrous magnesium sulfate. The product was further purified by then lyophilized to obtain compound 11:0 / CHRON 20760 = 01 using | Jot. mg tA = (product BUI TFA title in salt form 0 1

H NMR (400 MHz, METHANOL-D,): § 1.49 - 1.55 (m, 2 H), 1.55 - 1.61 (m, 2 H), 1.67 (m), 9 H), 232 - 239 (m, 1 H), 3.15 - 3.18 (m, 2 H), 3.27 (s, 3 H), 3.34 (dt, J=11.47, 2.64

Hz, 2 H), 3.81 (dd, J=5.96, 4.39 Hz, 2 H), 3.92 (d, J=3.12 Hz, 1 H), 3.95 (d, J=3.71 Hz, 1

H), 433 (s, 2 H), 4.51 (d, J=7.62 Hz, 2H), 7.28 (dd, J=9.08, 2.05 Hz, 1 H), 7.56 (d,

J=1.95 Hz, 1 H), 7.61 - 7.68 (m, 4 H), 7.85 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H) 5152; 00

Anal. Caled for CH, NO, S+27TFA+09 H,0: C, 46.40; H, 5.11; N, 6.68. Found:

C, 46.41; H, 5.05; N; 6.75. vo Jes - yl] —o— imidazole ju -151- (cyclopentylmethyl) -1-butyl [meV] - 0-methylbenzenesulfonamide. 7) Big N of

. Step A: 1 - [¥= »-butyl-1-(cyclopentylmethyl)-151-Jo imidazole-0yl] N=methylbenzenesulfonamide. 9 0 Laban slab mi l ee CCL NH H 0 0 Stirred 18 - ov} amino -4 - [(cyclopentylmethyl)amino] {Jed -18- methyl betzine sulfonamide (to know the method of preparation Refer to next steps b and c) 00) 0.175 mmol pH (J se and 0.0 ml trimethyl acetyl chloride (J se) 167 mmol) in an amount of ? ml of DCM containing a catalyst amount of (DMAP) at room temperature for one hour - the solvent was evaporated, and the product was then dissolved in ? ml of (ACOH) and then CG under 151 degrees The solvent was removed by evaporation, the residue was dissolved in EtOAc, washed with an aqueous solution of sodium bicarbonate, then with concentrated saline, and thinned with anhydrous magnesium sulfate. The product was purified by HPLC (Sad phase) using 0? - 9080 HHO / CHRON, and a freeze-drying process was conducted to obtain the title compound in the form of a salt (Y= pally BU TFA BG (oro ' H NMR (400 ME, METHANOL-D)): § 1.47 (m, 2H), 1.62(m, 2H), 1.68 (s, 9H), 0 (m, 4 H), 2.51 (m, 1H) , 3.28 (s, 3 H), 4.61 (d, J=7.42 Hz, 2 H), 7.30 (dd, J=9.08, 1.78 Hz, 1 H), 7.54 (m, 5 H), 7.68 (m , 1 H), 7.87 (d, J=9.18 Hz, 1 H); MS (ESI) (M+H) 2.05

ve.Anal.

Calcd for C,H; N.O, S + 1.5 178 + 9 H, 0: 2 52.92: H, 5.64; N, 6.96. ;426.2 D. 7.35; H, 5.51; N, Step B: ©« - 41-[recyclopentylmethyl)amino] -7-nitrophenyl) -8-Jer benzenesulfonamide. Ml 8 91 Oey > - Jg" N { bhi 0 NH £ : or Q stirred 18-(4-fluoro-7-nitrophenyl) N=methylbenzenesulfonamide ( For the method of preparation, see Example oF Steps B “c) (00 BG 1151 mM” (ds) and cyclotellylamine (0.0 167 mL of a solution containing 1 g/©mL” 1, 708 mmol)” and that in ?ml of BIOH containing a catalyst amount of (Yo) TEA 0 ml; 741 mmol) 0 under VO for 2 hours. The solvent was evaporated and the residue was dissolved in (EtOAc), then washed with Wo solution, 101150 (SW) and an aqueous solution of sodium bicarbonate »5 J stg. concentrated saline» and then dried with anhydrous magnesium sulfate. The crude product was purified by flash chromatography on a bed of silica gel using a 3:1 ELOXANE/EtOAc ratio as the separator (product = LA-ME 2051).1 NMR (400 MHz, CHLOROFORM-D): 5 1.31 (m, 3 H), 1.66 (m, 4H), 1.91 (m, 2H), 0 11 (m, 1 H), 3.13 (s,3 H), 3.24 (dd, J=7.23, 5.08 Hz, 2 H), 6.84 (d , J=9.37 Hz, 1 H), 2.28 (dd, J=9.28, 2.64 Hz, 1 H), 7.50 (m, 2 H), 7.60 (m, 3 H), 8.17 (m, 1 H) .. 7.45

a .0 step c”—N [©-amino-4-[(cyclopentylmethyl)amino]phenyl) N=methyl op sulfonamide. a i i are WH YRC m with NH NH dissolved 18 - }8 — [(cyclopentylmethyl)amino] -?-nitrophenyl) Jt N= betzen 0 sulfonamide (00 bh +61) mmol) in VO mL of EtOAc containing a catalyst of 9001 000. The solution was then shaken in hydrogen under a pressure of 40 psi and at room temperature for ? hours. As $9998 solution through a Celite layer and solvent removed by evaporation (Product = 1H 9644) 0441336026 MS (ESD): Example PY 0 - 1[?-—t-butyl =V= (cyclobutylmethyl) ju —HY— imidazole =0— [d= - —N methyl betzine sulfonamide 9 A ps : 0A Step A: t —¥] — N — butyl-1-(cyclobutylmethyl)-1579-Ju imidazole--0yl]-<-methylbenzenesulfonamide

~-and 101-: 9 | 0 Ob in milk TOA plus MH No. Follow the same procedures as Step A in Example Yo using oT} -N amino-4- AS [butylmethyl)amino]phenyl) N= Methyl betzine sulfonamide (for method of preparation see steps b c below) oY) bg 0107 mmol)” and trimethyl acetyl chloride 1.171 mL” VTA mmol) in ? mL of 72034 containing a catalyst amount of DMAP the product was purified by reverse-phase HPLC using 31 = 7080 0/07 and then lyophilized to yield the title compound in the form of the corresponding TFA salt (product = 47 pg Yoox 1 NMR (400 MHz, METHANOL-D,): 5 1.66 (s, 9 H), 1.92 (m, 2 H), 2.10 (m, 4 H), 11 (m, 1 H) ), 3.27 (s, 3 H), 4.65 (d, J=6.44 Hz, 2 H), 7.30 (dd, J=8.98, 1.95 Hz, 1H), 0 2.87 (m, 5 H), 7.68 ( m, 1 H), 7.81 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H) 412.3; Anal. 7.53 Calcd for C,H, N,0,S + 1.4 TFA + 0.8 H,0:C, 52.92; H, 5.51; N, 7.18. Found: C, H, 5.46; N, 7.11. : ;52.91 Step b: »1 - }€—[(cyclobutylmethyl) amino]-*-nitrophenyl)=N—methyl 0-benzene sulfonamide. 7 | 7 | ? Luba 0) “son of NH 5

AR 2 followed the same procedures as example (Fo step co using N = (4-fluoro == nitrophenyl) -N-methylbutzensulfonamide (for method of preparation see example oF steps b” c) (01+01 mmol); and cyclobutylmethylamine (+40 mL of a solution of 8,1/MeOH 4 00 mM) in 1 mL of EtOH containing 1 YO)TEA mL 0 mM VEY mall). The crude product was purified by flash chromatography on a silica gel bed using a hexane/EtOAc ratio of ?:1 as the eluting (product = 61 pg (Y044 H), 1.81 (m, 2 H) , 1.95 (m, 1 H), 2 ) 1.56 H MHz, CHLOROFORM-D: 0m4) 'H NMR (m, 2 H), 3.13 (5, 3 H), 3.33 (dd, J=7.23, 5.08 Hz, 2 H), 6.83 (d, J=9.18 Hz, 1 H), 2.19 (dd, J=9.18, 2.54 Hz, 1 H), 7.51 (m, 2 H), 7.61 (m, 3 H), 8.04 (m, 1 H). 7.45 0 Step C: <- (*-amino-4-[recyclobutylmethyl)amino]phenyl) Jr ~N= betaine-sulfonamide. acs 0: = 2 NH, og.

Oe NH KH ng ag Example procedures were followed (vo step c; using —N }8-[(cyclobutylmethyl)amino]-3-nitro {Jd-28-methylbenzenesulfonamide 0A) with 1154 mmol Hb) in 01 mL VO of EtOAC containing a catalyst of LCRA 9601 (for product = MS (ESI) 044 (ot oF) (M+H) ) 346.20

-1110- - Ex. 17 —-t—Y ] -N-butyl -\ — ) -Y cyclohexylethyl) —\ 0-bazimidazole JH] —N—methylbenzene sulfonide . il Oris peas g NB 0 [?- )-butyl N= (7-cyclohexylethyl)-151-bizimidazole -*-yl]-0<-methylbenzenesulfonide . 0 for Other Or OS: (I followed the same procedures as step a in the oo example using oN ©-amino-4-[(7-cyclohexylethyl)amino] {Je-28-methylbetzine-sulfonamide ( For the method of preparation, see the next steps b c (0) in M21 mmol)” and trimenheyl acetyl chloride (07 ml 160 mmol) in ? ml of DOM containing a catalytic amount of DMAP. The product was purified by HPLC with a Sal phase using 01 = M. 9708 10/007, then this product was freeze-dried to obtain the title compound in salt form. Corresponding TFA (product = YY meat (Soto

-117- a 1

H NMR (400 MHz, METHANOL-D): § 1.11 (ddd, J=23.92, 12.11, 2.83 Hz, 2 H), 1.34 (m, 3 H), 1.60 (m, 1 H), 1.66 (s, 9 H), 1.72 (m, 1 H), 1.77 (m, 1 H), 1.81 (m, 2 H), 1.85 (m, 2 H), 1.90 (m, 1 H), 3.27 (s, 3 H) ), 4.60 (m, 2 H), 7.33 (dd, J=8.98, 1.95 Hz, 1 H), 7.54 (m, 5 H), 7.68 (m, 1 H), 7.74 (d, J=8.98 Hz, 1H); MS (ESI) (M+H) 454.2; Anal.

Calcd for C,H, ,N.O,S + 1.4 TFA: C, 56.40; H, 5.98; N, 6.85. Found: C, 56.48; H, 5.98: ©

N, 6.99. —N— amino]-?-nitrophenyl) (Jus step b: 8 - }£— ]= cyclohexyl methylbenzene sulfonamide o 8 7) 8 no is mer Kes

Ooh SX

SOL — . 2 —_ fluoro-nitrophenyl) 6) -N line b b = using J (Yo) I followed the same procedures as example 1 01) steps b c) oF methyl betzine sulfonamide (to know the method of preparation See Example 7- BGY (11 mmol neighborhood); and (7-cyclohexylethyl)amine hydrochloride 407 mL 1,0 NV) TEA containing BIOH mMol) in ? mL of 7 mol). The crude product was purified by flash chromatography on a layer of silica gel 2697 (To = gall) as a separating material 1:4 using Mxane/M8:08 in a ratio of 0.

-11?- « 1

H NMR (400 MHz, CHLOROFORM-D): § 0.99 (m, 2 H), 1.25 (m, 4 H), 1.43 (m, 1 H), 1.64 (m, 3 H), 1.72 (m, 1 H) ), 1.75 (m, 2 H), 1.78 (m, 1 H), 3.13 (s, 3 H), 3.33 (m, 2 H), 6.83 (d, J=9.37 Hz, 1 H), 7.46 (m , 1 H), 7.51 (m, 2 H), 7.58 (m, 2 H), 7.61 (m, 1 H), 8.08 (m, 1 H). -<- Cyclohexylethyl)amino]fibryl)Vy] == amino =v} -< D Step C: Methylbetzine sulfonamide. z

CG 13 0 i | Ma i | :

NH i.e. step c Using 17- (4-] = cyclohexyl Fo I followed the same procedures as example mmol) 1.144 methylbenzene sulfonamide (10 pH) N= {Jd amino] -3-nitro (Jd ( Yield = 01 in C/Pd 9000 on a catalytic amount of pH EtOAc ml of VO in 0

MS (ESI) (M+H) 388.26. 005

A Example - imidazole jo -151-butyl -t ?- - (JY benzylpyrrolidine -1) -1[-methylbetzine sulfonamide. —N— ]-8

-114-" 7 0 Sap No: 14 M -1(-1[-Nag[-Bazylpyrrolidine -*-yl) -?- ;-butyl-21-bizimidazole —0— yl] —N— methylbenzene sulfonamide z 9 b z FN WH, ¢ Ys nN i — ELAR m NH oF ave © followed the same procedures as in step a in the example (Fo using =F} oN Amino-4 - ee -1([pyrrolidine -*-yl)amino]phenyl) N= methyl betzine sulfonamide (for method of preparation see steps b z below) ) Yo vy, 'VY mM “(Js, trimethylacetyl chloride 0.0 YO) mL” VAS mM) in © mL of 0014 containing a catalytic amount of .DMAG and the product was purified using HPLC with reverse phase by 01 (H,O/ 03:07 7010 - 0) with freeze drying to obtain the title compound in the form of salt BU TFA (for product = tA pg oto 1 H NMR (400 MHz, METHANOLD3: § 1.59 (s, 9 H), 2.61 (m, 1 H), 2.72 (m, 1 H), 3.23 (m, 3 H), 3.44 (m, 1H), 3.66 (m , 1 H), 3.75 (m, 1 H), 3.81 (m, 1 H), 4.44 (m, 2 H), 5.85 (m, 1 H), 7.23 (dd, J=8.89, 2.05 Hz, 1 H), 7.43 (m, 4 H), 7.51 (m, 6 H), 7.65 (m, 1 H),

-11 < (d, 1-7.81 Hz, 1H), MS (ESI) 1032+ 503.2: Anal.

Calcd for C2sH34N202S +3 7.94 TFA + 0.3 1120: C, 52.39; H, 4.83; N, 7.27. Found: C, 52.44; H, 4.87; N, 7.28, step b: «- 67 - 1-([bzyylpyrrolidine -*”-yl)amino] 7nitrophenyl) - © <- methylbetzinesulfonamide 8.81 2 a | 8": in Neg -N Nam 0 1D 9 — 106 1 0 - \ I followed the same procedures as for example Yo in step b using -N ( ¢ -— fluoro — "-nitrophenyl) - 7<- methyl betzine sulfonamide (for method of preparation see example OF Steps b “c) (0 pH TY mmol)” and 1- benzylpyrrolidine “Y=amine (0E 0 pH 0.77/ 1 mmol) in 7 mL of 26011 containing TEA (0 0.05 mL 1.774 mmol). The crude product was purified by flash chromatography on a silica gel bed using 0 — 2M908 EtOAc in lysate = q0 = h...and 4669 MS (ESI) (M+H) step c: —N }¥— amino -- -1([bepazylpyrrolidine —¥= yl)amino]phenyl) = —N 10 methylbenzenesulfonamide

2 = \ 3 _ A g 1 9 Oe Cee ' NH NH mm AS I followed the same procedures as the example ove step c using bj -1([ EAN borolidine - »- yl) amino ] -3-nitrophenyl) (N= methylbenzene sulfonamide (20 pH 0.704 mmol) in Vo ml of 3:06 containing a catalytic amount of © C/Pd 70101 (for product - 1L 70/85) ) .437.02+ MS (ESD (M+H) Ex. Ye =e —Y} -<butyl -1-[(4,4-difluorocyclohexyl)menyl] = mB basimidazole —0— yl) —N—methylptyrene sulfonamide Others N = es og F 0 Step A: -N (7-p-butyl-1 -[(4,6-difluorocyclohexyl)methyl]-1b imidazole —0—yl)methylbenzene sulfonamide

-117- 4 | 7 3 N 104 H, SN N e l | 0 0 y N lute 6" 6" F F I followed the same procedures as in step of example (Yo using a <- ) = amino + } (8,6 = difluorocyclohexyl)methyl] Amino (phenyl) N= methylptyrene sulfonamide (for method of preparation see step B C D E GU) TY bm 11495 mmol)”; 0 and trimethylacetyl chloride (mL AT mmol) in ¾ mL of DCM containing a catalytic amount of DMAP. The product was purified by reverse-phase HPLC using Corl «H,O/CH; C.N.Y.A. - 08 After that, the Cait process by freezing to obtain (JOYA in Yo = mally BULL TFA) the title compound in the form of salt 1:

H NMR (400 MHz, TM: 7p § 1.57 ) 2 H), 1.67 (s, 9 H), 1.72 (s, 2 6 (m, 1H), 1.80 (m, 1 H), 2.07 (m ,2H),2.24(m,1H),3.27(s,3H),4.54(d,J=7.62Hz, 2 0

H), 7.31 (dd, J=8.98, 1.95 Hz, 1H), 7.54 (m, 5H), 7.68 (m, 1H), 7.86 (d, J=8.98 Hz, 1

H); MS (ESI) (M+H) +476.0; Anal. Calcd for C2sH31N302S8F2+ 1.6 TFA: C, 51.47; H, 4.99: N, 6.39. Found: C, 51.46; H, 5.00; N, 6.53. Step B: —t-butyl[(4,6-difluorocyclohexyl)methyl]carbamate H NO iy conjugate y Y 0 © ——_ FF \o 0

. Hm-1 of dissolving 4-17-Boe-aminomethylcyclohexanone (1g; 4.4mmol) in 10ml of DLM under Shs°C; Then 11 drops of (JV, £0) DAST mmol) were added and the solution was stirred under room temperature overnight. The aqueous solution J lms of 101180, 908 was washed with a saturated sodium bicarbonate solution and concentrated 0% saline, then dried with anhydrous magnesium sulfate. The crude product was also purified by flash chromatography on a layer of silica gel using a solvent: EtOAc at a ratio of ?: 10 as an eluent (for C08 Ai product (Pot 1 H NMR (400 MHz, CHLOROFORM-D)) : § 1.19 - 1.36 (m, 2 H), 1.44 (s, 9 H), 1.51 - b 3.03 (m, 1 H), 1.59 - 1.75 (m, 2 H), 1.75 - 1.84 (m, 2 H), 2.01 - 2.16 (m, 2 H), 1.56 J=6.54 Hz, 2 H), 4.62 (br.s, 1 H). 01 Step C: [(4,4-difluorocyclohexyl) ) methyl]amine hydrochloride i NO Ni, YY : 0 and CISP FF FF stirred ;-butyl[(4,4-difluorocyclohexyl)methyl]carbamate)000 (et 0" mmol) in ¾ ml of ACOH/@M) HCL at room temperature for 2 hours. 10 Then the solvent 5 was evaporated, the residue was washed with ether, filtered, and then thinned (product = TT BGY (JOAN

-118- “1

H NMR (400 MHz, METHANOL-D«): § 1.28 - 1.40 (m, 2 H), 1.71 - 1.82 (m, 2 H), 1.84 (d J=3.12 Hz, 2 H), 1.86 - 1.89 (m , 1 H), 2.03 - 2.15 (m, 2 H), 2.85 (d, J=7.03 Hz, 2

H). nitro =P {el difluorocyclohexyl)methyl]-4,4[1 — 8) —N step d: 0phenyl)-<-methylcage sulfonamide OEE OK The neighborhood of BiH og 4 followed the same procedures used in the example (Yo step b” using 17- (4-Fluoro-*-nitrophenyl) N= methylbutzensulfonamide (for the method of preparation see Example: steps b (c) (00 VY + mmol)” and [(4,4-difluorocyclohexyl)0methyl]amine hydrochloride (Y0)gm” AT (+0 mM). mol) in 7 ml of SAH BIOH on TEA (007 ml, +407 mmol). The crude product was purified by flash chromatography on a silica gel bed using %¢% EtOAc nihexane as the separation material (F084 BGY = sequential VY (for product) H NMR 400 MHz, CHLOROFORMDY: E 1.42 ( m, 2 H), 1.71 (m, 1 H), 1.80 (m, 2 H), 1.92 (m, 1 H), 1.96 (m, 1 H), 1.96 (m, 1 H), 2.17 (m, 2H), 3.13 (5,3H), 3.24 (dd, ©

J=6.64, 5.66 Hz, 2 H), 6.82 (d, 19.18 Hz, 1 H), 7.48 (m, 2 H), 7.51 (m ,2 H), 7.61 (m, 3

H), 8.20 (t, J=5.27 Hz, 1 H).

-176- = step H: goal -©( —N -- ([(6,4-difluorocyclo(Jen methyl] amino)—N— (Jeb methylbenzenesulfonamide © 7 | ?

I followed the same procedures as in the example (Fo step or using rs N } - £) ~N 0 difluorocyclohexyl)methyl[amino]-7-nitrophenyl) N=methylptyrenesulfonamide

(10 pgA mmol) in 10 mL of EtOAc containing a catalyst amount of 101%

MS (ESD) (M+H) «410.24. 2044 Product = Dah Ai. 0

Example 64:

“-[-; = butyl-1-(lypyridine-4-butyl)-81-biz imidazole ~~ yl]

0 “<< -methylbenzenesulfonamide NP N PDO EIA > N Step A: 1 ]= + -butyl -1- (pyridine == ylmethyl) -159-jo Imidazole N= [fy -*-methylgape sulfonamide

-171- 0 Any BH, any oo © COAL A 8 or 0 I followed the same procedures used in step of eg (Fo using -03) AN amino t= — [(pyridine-4 = ylmethyl)amino]phenyl) N= methylbenzenesulfonamide (for method of preparation see next steps bc) (19 WV + mM (dar) and trimethylacetyl chloride VAM ry Y0) 0 + 5 mmol) in 0 mL of DCM containing a catalyst amount of DMAP and the product was purified by reverse-phase HPLC using HO 701 = 01 07, 03 and then purified Freeze-drying thereby obtaining the title compound in the form of BULLI TFA salt (product = 48 NH (Yoo) I H NMR (400 MHz, METHANOL-Dx4): § 1.57 (s, 9 H), 3.22 ( s, 3 H), 6.08 (s ,2 H), 7.13 (dd, 18.88, 2.05 Hz, 1 H), 7.29 (d, J=8.40 Hz, 1 H), 7.38 (d, J=4.88 Hz , 2 H), 7.49 (m, 4 \ H), 7.53 (m, 1 H), 7.63 (m, 1 H), 8.62 (m, 2 H); MS (ESI) (M+H)+ 435.0;

Calcd for C24H26N402S + 2.3 TFA + 0.1 H20: C, 49.17; H, 4.11; N, 8.02. Found: C, 49.15; H, 4.10; N, 8.08. |Step B: ——N-methyl =F} —N=nitro —€—[Rabiridine-4-ylmethyl)amino] {Usd 0 benzenesulfonamide

-17- a 7 | 0 0 9 . aa | 3] 1 7-4 MN. .- — .

Obl — Opa

F NH or

N

Methylptyrene sulfonamide (for a known method, N= nitrophenyl) Ff -4( NE done al) —_ gy “(Js m 0 and 77 Ces 101 © ) dl Steps b al Preparation See an example of millimoles) in ? mL of 011:07 at temp 1.27/0 mL (V) methyl)pyridine 0

EtOAc residue was left in cdl then Cull for 1 hour. Then the room was evaporated for © concentrated saline and dried by J sls. 5 aqueous sodium bicarbonate J shes, and washed Anhydrous magnesium sulfate.The crude product was also purified using flash chromatography BG 011 - on a layer of silica gel and using 280/88 as separator.(Product 20/7 1

H NMR (400 MHz, CHLOROFORM-D): 5 3.13 (s, 3 H), 4.61 (d ,/-5.08 Hla 212, 665 00 (dd, J=9.08, 1.07 Hz, 1H), 7.25-7.29 (m, 2 H), 7.37 (dd, J=9.18, 2.73 Hz, 1 H), 7.47 - 7.53 (m, 2 H), 7.56 - 7.59 (m, 2 H), 7.60 - 7.65 (m, 1 H ), 7.70 (d, /=2.54 Hz, 1 H), 8.50 - 8.54 (m, 1 H), 8.62 (d, J=5.47 Hz, 2 H).ger N= step c: «- (*- Amino-6-[Rabiridin-6-ylmethyl)amino]phenyl)benzenesulfonamide.0

177 - . (©-nitro-4-[(pyridine-4-ylmethyl)amino]phenyl)ptyrene sulfonamide (97 pg 41 mmol) in VO ml of EtOAc containing a catalytic amount of 207001 0. © Producer = Aa (YOY) .368.94 RT (ESD) Ex. City <-methyl-1[-N-tetrahydro—HY—pyran-4-ylmethyl) = = (trifluoro ju -151- (Jobo imidazole —0— yl]benzene sulfonamide. guy NH 81. NF Ach 1 NF F -——— § 0 A solution of -28 was heated ( ©-amino-4-[(tetrahydro-?11-pyran-4-ylmethyl)amine] phenyl) N= methylbetzine sulfonamide (11,7 v 177 mmol) (for method of preparation see Steps B” C In an example (VY) in trifluoroacetic acid (7) (Jr) for 1 ? hour under reflux temperature. After evaporation, the material (ial) was purified by reversed-phase HPLC using 8 .9/67 0107 (H0/) Those

-172- The material by annealing to obtain the title compound in the form of TFA salt Nazer (product = YAY in Hayy 2007) 1 H), 2.16 - 2.33 (m, 1 H), 3.25 (s, 3 H) ), 4 penh) 1.50 - 1.40 e H NMR (400 MHz, CDsOD): (m, 2 H), 3.86 -4.00 (m, 2 H), 4.32 (d, ]=7.62 Hz, 2 H ), 7.32 (dd, J=8.88, 3.41 - 3.31 Hz, 1 H),738(d, J=1.76 Hz, 1 H), 7.48 - 7.58 (m, 4 H), 7.62- 7.69 (m, 1 H), 7.72 0 2.05 (d, J=8.79 Hz, 1 H). MS (ESI) (M+H)= 454.0. Anal.

Calcd for C2iHz2FsN303S+ 0.20 TFA (476.29): C, 53.97: H, 4.70; N, 8.82; Found: C, 54.01; H, 4.73; N; 9.00, ex 0:67 —N [?- 1, 1( - difluoro -1- (J))13hydro-157-pyran (die f= 0 - 1k-ju imidazole -#-yl] N=methylbenzenesulfonamide gy N FCA 0 Diisopropylethylamine (1.49 * mg 44 mmol) was added to Lol A EB pd -4- [(Nitrahydro-137-pyran-4 = ylmethyl)amino]phenyl) N= methylbetzine sulfonamide (5,7 pH” 1,710 mmol) (for method of preparation see Steps B » C; Ve 0 e_in Example (8) YY difluoropropionic acid (YY) with a neighborhood of 1.71 mL (Js in DMF (© ml) at zero degrees Celsius with stirring for a period 1 minute. Then add to

-1?e-a mmol). The reaction mixture was stirred throughout the period of 0, YE mg (41.7 HATU) overnight at room temperature. After evaporation of the solvent, the remaining substance was dissolved in acetic acid. The substance gd was diluted for an hour at a temperature of 0 m. After evaporation of VY ml) with heating for (10 (JV) @N) ml) and then washed with sodium methoxide 001 (residual with M 806 ml); Then it was diluted with sulfate (XY 01) and a saturated solution of sodium chloride (0) using anhydrous sodium HPLC. After filtration and concentration. The crude product was purified by layering on a layer of silica gel to obtain a 1:1 acid, with a ratio of EtOAc/hexane of the title compound in the form of a white solid. (70175) 1

H NMR (400 MHz, CDsOD): § 1.28 - 1.45 (m, 41, 2.08-2.15(m, 1H), 2.21,

J=19.53 Hz, 3 H), 3.13 - 3.19 (m, 2 H), 3.19 (5, 3 H), 3.80 (m, 2 H), 4.28 (d, 17.42 Hz, 2 00

H), 7.13 (dd, J=8.79, 1.95 Hz, 1 H), 7.36 (d, J=1.95 Hz, 1 H), 7.47 - 7.52 (m, 2 H), 7.53 - 7.63 (m, 2 H) ,7.67- 7.73 (m, 1 H), 7.75 (d, J=8.79 Hz, 1 H). MS (ESI) (M+H) +=450.0.

Anal. Calcd for C22H25F2N303S (449.52): C, 58.78; H, 5.61; N, 9.35; Found: C, 58.94; H, 5.51; N, 8.94. (EY mal 0 -11,,7(pyran-4-ylmenheyle) -?- —HY = methyl -7<- ]= (tetrahydro —N trifluoroethyl) -151-bz Imidazole —0—yl]benzene sulfonamide

* -1?1- F . | 4 post 0 I followed the procedures for Example 47 using 77 =v}amino-4-[(tetrahydro-117-pyran-4-ylmethyl)amino] {ed-13-methylbutzensulfonamide) 1000 mg 40 0 mmol) (for the method of preparation, see steps b, c, d, e in Example 41)”; diiso (Jap 0 ethylamine 11 Ay (AA) mmol)” and 7,7,7-trifluoropropionic acid (0,7 pH 1,44 mVAY, 1) HATU (Jr p. 8A; mmol) in 4t 10(Jo and thereafter acetic acid (0ml). The crude was purified by MPLC using EtOAc on a silica gel bed to yield 416.4 Baham (TY) of the title compound as a light yellow solid. H NMR (400 MHz, CDs0OD): § 1.39 - 1.65 (m, 4 H), 2.12 - 2.30 (m, 1 H), 3.25 (s, 3H), 0 (m, 2 H), 3.88 - 3.96 (m, 2 H), 4.22 ) J=9.96 Hz, 2 H), 431 (d, J=7.62 Hz, 2 3.38- 3.32 H), 7.22 (dd, J=8.89, 2.05 Hz, 1 H ), 7.39 (d, 121.56 Hz, 1 H), 7.49 - 7.59 (m, 4 H), 7.63 - (m, 1 H), 7.70 (d, ]=8.98 Hz, 1 H). MS (ESI) (M+H)+=468.0. Anal.

Calcd for 7.68 CH24F3N303S+1.10 TFA+0.20 H20 +0.20 CHsOH (602.95): © 48.61; H, 4.40; N, Found: C, 48.59; H, 431; N, 6.85. \o ;6.97 Example 66:

17-O-7 imidazole-5-yl]ju-151-(ethyl)(-1)-7-(cyclohexylmethyl)-1[-N-betsulfonamide 5M [(mM cyclicylamine = amine mY} SN using oF followed the procedures of Step A in the example of live DMAP (VO) “(Jr mM 1.51 methyl)amino]phenyl)butylsulfonamide ( 184 pH 0 in Tet 0 (Jr with 500 + mM VE); mmol)” and 7-ethylbutyryl chloride Y

MPLC ml). The crude product was purified by (V0 ml); Then in acetic acid V0) on a layer of silica gel. Product = 41.4 by 1:1 using HEXAN / 06:2 ratio

Jovy!

H NMR (400 MHz, CDsOD): 0.92 (t, J=7.42 Hz, 6 H), 1.18 (m, SH), 1.57 (m, 2H), 0 1.73 (m, 3 H), 1.83 ( m, 2 H), 1.94 (m, 3 H), 3.33 (m, 1H), 4.26 (d, J=7.62 Hz, 2 H), 7.25 (m, 1H), 7.48 (m, 2 H) 7.57 ( m, 2 H), 7.73 (d, J=8.98 Hz, 1 H), 7.81 (m, 2 H). MS (ESI) (M+H)+ = 440.0. Anal. Calcd for C2sH33N3025+1.10 TFA+0.10 H20 (566.85): C, 57.63;

H, 6.10; N, 7.41; Found: C, 57.56; H, 6.11; N, 7.45. go Example 01

-1?/- - - Pepsimidazole mH = (Egilpropyl) -1(hexylmethyl) -?-Wolkes(”-1[ -< methylbenzenesulfonamide. —N— yl ] 8 l 1 of Jl-1((cyclohexylmethyl)-?-1] AN using (VF followed eg procedures with 184 mmol HCl) Ao , 4( sulfonamide ago imidazole -*-yl] ju -131- propyl) © Beghi 060 Kaif (YLT) and sodium hydride (VF) (to know the method of preparation, see example = ml) ( product 01(THF mmol) in 1587 mmol)”; iodomethane (87.7/ pH) (TFA pH 9079 as a white solid of salt 4 H NMR (400 MHz, CDsOD: 0.95 (t, J=7.42 Hz, 6 H), 1.21 (m, 5 H), 1.61 (m, 2 H), 1.71 (m, 1 H) 1.76 (m, 2 H), 1.86 (m, 2 H), 1.99 (m, 3 H), 3.27 (s, 3 H), 3.38 (m, 1 H), 0 433 (d, J=7.81 Hz, 2 H), 7.29 (m, 1 H), 7.53 (m, 2 H), 7.57 (m, 3 H), 7.68 (m, 1 H), 7.83 (d, J=8.98 Hz, 1 H).MS (ESI) (M+H) + = 454.2.Anal.Calcd for C26H3sN3025+1.00

TFA+0.20 HzO (571.28): C, 58.87; H, 6.42; N, 7.36; Found: C, 58.85; H, 6.54; N, 7.24. 16 Example - yl] —o— imidazole ju —HY— (cyclohexylmethyl) -1-butyl —t—Y] -N 0 ethylbenzenesulfonamide. —N

-\Ya- .

Ql 0 1 has 0 - (cyclohexylmethyl) -1- using 77[7- +- butyl VF followed the example mmol procedures (to know the NYY Biz imidazole method -* - YL]btzensulfonamide (01 pH 121 pH 97010 808 mmol); preparation (YT) (see Example 7)” and sodium hydride (EV A = ml). Product A) THF mmol) at 1779 pg 0V,Y © Yodo Ethan

TFA for slay salt in solid form 4 1

H NMR (400 MHz, CDsOD): § 1.08 (t, J=7.13 Hz, 3H), 1.25 (m, 5H), 1.62 (m, 2H), 1.67 (s, 9H), 1.71 (m, 1 H,) 1.78 (m, 2 H), 2.10 (m, 1 H), 3.74 (q, 17.03 Hz, 2 H), 4.45 (d, J=7.62 Hz, 2 H), 7.22 (dd, J= 8.98, 1.95 Hz, 1 H), 7.49 (d, J=1.56 Hz, 1 H), 7.54 (m, 2

H), 7.60 (m, 2 H), 7.66 (m, 1 H), 7.85 (d, J=8.98 Hz, 1 H). MS (ESI) (M+H)+=454.0. 00

Anal. Calcd for C2sH3sN3028+1.10 TFA+0.20 HzO (582.68): C, 58.13; H, 6.31; N, 7.21;

Found: C, 58.15; H, 6.41; N, 6.99.

EV Example - tetrahydro-1-pyridine-?-ylethyl)-1-methyl-1(-7[oN-methyl WN imidazole -0-yl]benzene sulfonamide. ju -159 - biran - 6 - yel miguel) —HY 0

1! - Solve Oph ex N 0 of : Step A: —N methyl -1( —Y] N= methyl -0-pyridine -?- ylethyl) = = (tetrahydro—HY—pyran-4-yl meghel)-151- jm imidazole == yl]bensulfonamide. ‎MN; N Quy Ne b 0 1 This is the way to go

TM NCE methyl-1(SY methyl-1-pyridine-7-ylmethyl)TV (tetrahydro-HYpyran-4-ylmethyl) = jo =H imidazole m = amine hydrate and chloride (9 pg/LAY mmol) For information on the method of preparation, refer to the following steps (see the following steps): (of 18) DMAP #7 mM)” and benzenesulfonyl chloride (87 pH” 0.77 mM 0 mol) in MeCN (0 mL); for a period of A hours at room temperature. The reaction mixture was quenched with water (? (Jo) and after evaporation the residue was purified by Sand-phase HPLC using © H,0/ CH;CN 907 o — 1 5 Freeze drying was carried out to obtain on the title compound in the form of salt BU TFA (Product = 00 bg

(Y01A

_ \ 7 \ -— 2 1

H NMR (400 MHz, CD30D): 1.02 - 1.22 (m, 5 H), 2.01 (s, 6 H), 2.96 - 3.10 (m, 2 H), 3.28 (s,3 H), 3.70 - 3.81 (m, 2 H), 3.93 (d, J=6.83 Hz, 2 H), 7.25 (dd, J=8.98, 2.15 Hz, 1

H), 7.39 -7.47 (m, 1 H), 7.50 - 7.60 (m, 5 H), 7.64 - 7.76 (m, 4 H), 7.91 - 7.99 (m, 1 H).

MS (ESI) (M+H)+ = 505.0. Anal. Calcd for C2sH32N4O3S+1.0 TFA+0.2 H20+0.4

CH3OH (635.10): C, 57.49; H, 5.55; N, 8.82; Found: C, 57.52; H, 5.46; N, 8.72. o Fluoro == nitrophenyl)acetamide: Z-6) —N Step B:

H

HN NO N

CC 2 ~ NO,

F2. mol) in parts to acetic + YAN added 4-fluoro-#-nitro-aniline (£0 g” ml) under room temperature. The mixture has been stirred. The reaction is under (Vor) anhydride hob at room temperature for two hours; Then the white solid was collected and stirred in vacuo 0 (Yov 0 to obtain the title compound) 2 grams; 1

H NMR (400 MHz, CDCI): 6 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44 , 2.73 Hz, 1 H). Methylacetamide —N— fluoro--*-nitrophenyl) —£) —N Step C: 1 7 Tr — ~" MC, 0 3 0 g

Vo

-1"7- - parts of sodium hydride (80 Y g » 9070 60 mmol) were added to a solution of “N (4-fluoro-7-nitrophenyl)acetamide (9.97 g” 40 mmol) in THF (VY ml) under zero degrees C. With stirring for 310 minutes, iodomethane (AY) g (11 mmol) was added and the reaction mixture was stirred under room temperature for two hours, then Mixture 0 was quenched with a saturated solution of sodium bicarbonate (Jo 7 1) and subsequently extracted with EtOAc 001 XT mL. The combined organic phases were washed with a saturated NaCl solution (F XY = mL) After filtration and concentration, AVY Haram (9610) was obtained.

From the title compound 0 formed a brown solid. (s, 3 H), 3.30 )6, 3 H), 7.38 ) 1 H), 7.52 ) 1 H), 1.29 e'H NMR (400 MHz, CDC): (s, 1 H) . Vo 7.95 Step D: ——N methyl =F} N= nitro —€— [(tetrahydro —HY— pran -;- yl

Methyl)amino]phenyl)-acetamide. Co Yee YC” _— a © N F 0 0

4-aminomethylpyran (; 1.9 g” 117 mmol) was added to a mixture containing <- Vo-(4-fluoro-”-nitrophenyl)—N=methylacetamide (4,711 g” YN, TY millimoles); and sodium carbonate (0.00 grams” EV, mmol) in 20011 VY (ml) at room temperature. The reaction mixture was heated for oUF below 10 °C. And after steaming

=\YY-”

Ethanol The residue of (Jr £1 +) BtOAC was dissolved, washed with water (1 ov x ml)” and a saturated solution of sodium chloride (0 XT © ml)” and then dried with sodium sulfate. After filtration and concentration, 6.57 grams (OV) of compound were obtained

The address is in the form of an orange ade. 1 2H (1.72) - 1.81 (m, 2H), 1.90 (3, 3H), © n 1.52 - 1.38 E for H NMR bait (400 MHz, (m, 1 H), 3.23 (5, 3) H), 3.23 - 3.27 (m, 2H), 3.36 - 3.49 (m, 2H), 401 - 4.07 2.02 - 1.93 (m, 2H), 6.91 (d, J=9.18 Hz, 1H), 7.29 (dd, /=9.08, 2.64 Hz, 1 H), 8.05 (d, J=2.34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H).MS (ESI) (M+ H)-= 309.12, : Step H: =F} —N-amino-5-[(tetrahydro—HY—pyran —€— ylmethyl)amino]

0 Phenyl] Jos —N— Acetamide. NH, B NO, Ab Is 0 0 14methyl-N—}35-7-4-[(tetrahydro-117-pyran-4-yl(dior-amino]phenyl) has been hydrogenated acetamide (07a g) VY mmol) in ethyl acetate (Ye ml) catalyzed by 0090© (Y), + g) at a hydrogen pressure of 0 - 460 psi in a V0 apparatus UM Parr for VA 1 hour at room temperature. After filtration through the Celite layer and after concentration, 1 001 (20) gram of HCL salt used in the next step was obtained without purification.

14 “ 1 H NMR (400 MHz, CD30D): § 1.32 - 1.46 (m, 2 H), 1.78 - 1.84 (m, 2 H), 1.85 (s, 3 H), (m, 1 H), 3.16 (d, J=6.83 Hz, 2H), 3.20 (s, 3H), 3.39 - 3.51 (m, 2H), 3.94 - 2.06 - 1.91 (m, 2H), 7.01 (d , J=8.59 Hz, 1 H), 7.12 (d, J=2.15 Hz, 1 H), 7.17 (dd, J=8.49, 4.39 4.03 Hz, 1 H), MS (ESI) (M+H) +: 278.7 0 Step f: <-methyl N= [7-(pyridine Y= ylmethyl) -1-(tetrahydro = “HY pyran-6-ylmethyl) = HY Biz Imidazole =0— yl]acetamide. z by 1 ra TC ra ? 0 0 Followed the procedures for example “01 using 78 =v}amino-4-[(tetrahydr-117-pyran-4-yl-methyl)amino]phenyl)-27-methylacetamide hydrochloride (41,711 bg1, 71 per 0 mol)” and 3?- pyridyl acetic acid hydrochloride (4 YAR with a volume of “1.65 mM” (dar and diisopropylethylamine AV) with a pH of 7.8 mmol); HATU (180 mmol VAY pH) in (Je V0) DEM and then in (01 ml) acetic acid. The crude product was purified by MPLC using MeOH/ EtOAc at a ratio of 1:710 on a layer of silica gel to obtain 0801 BaH (7011) of the title compound in the form of a yellow pulp 0 color MS (ESI). ) (MH) = 379.0

1:0 step oN methyl-1(-7[N=methyl-1-pyridine JY ethyl) Y=(tetrahydr—HY—pyran-4- (yl-methyl)ju —HY— imidazole —0— yl]acetamide. 1 NO | RA Yor ved Q 5 30 N 0 0 1 (10 KHMDS mL” 8 4 A mmol) was added to a solution of 7<-menel N=[?-©(pyridine-?- (ylmethyl) -1- (nitrahydro-137-pyran-4-ylmethyl) = THY petyrimidazole -#-yl]acetamide (4 YEA, pH 5107+ mmol) in YO) THF ml) under pay-VA stirring for 10 minutes added iodomethane (NATL) (g #0 μl 0.88 mmol). The mixture was stirred for −1 min at -L °C and for 31 minutes at room temperature, then the mixture was cooled again to -8 °L and another 0.17 0 eq of KHMDS with iodomethane was added to it . The resulting mixture was stirred for 71 min at -8 °C and 0 £ 0 min at room temperature.” Then the mixture was quenched with a saturated solution of sodium bicarbonate (0 mL) and then extracted with (I) BOA * 70 mL) . The combined organic phases were washed with a saturated solution of sodium bicarbonate (TY) ml). and a saturated solution of NaCl (Yo) mL) and dried with 0 sodium sulfate. After filtration and concentration, the residue was purified by MPLC using MeOH EtOAc at a ratio of 1 T+ on a bed of silica gel to yield 718:1 BaM (7080) of the title compound in the form of a white solid.

-1- - 1

H NMR (400 MHz, CDCL): § 1.02 - 1.12 (m, 2 H), 1.13 - 1.19 (m, 2 H), 1.19 - 1.27 (m, 1 H), 1.90 (s, 3 H), 1.97 ( 5, 6 H), 2.90 - 3.11 (m, 2 H), 3.31 (s, 3 H), 3.68 (d, J=7.22 Hz, 2

H), 3.81 (m, 2 H), 7.04 (dd, /=8.49, 2.05 Hz, 1 H), 7.18 - 7.32 (m, 3 H), 7.57 - 7.70 (m, 2

H), 8.53 - 8.70 (m, 1 H). MS (ESI) (M+H) = 407.03. (Testra = N= (Jt bipyridine-?-yl-1-methyl-1) (Step H: <-methyl-?-©hydro—HY—pyran-4-ylmethyl) -159- Ju imidazole-8-amine L|1 4 N ~ 0 — HN 1 LC — <> B 1 pg —_— L 8 1 -117- (tetrahydro - 1- (Jed pyridine == yl-1)-7[N= methyl NaS 0.977 mM YY 4(yl]acetamide mom imidazole ju HY = pyran-4 - ylmethyl) and then heat 1:7 in a ratio of ON) and hydrochloric acid (BtOAG mol) in * mL of a mixture of 0

Personal Chemistry Smith The mixture was heated at 1101°C in a 2-kilogram microwave oven and dried in a vacuum, A, for one hour. And after aad and that Synthesizer BHM (20100) from the title compound in the form of a white solid TTY obtaining grey. 1

H NMR (400 MHz, DMSO-D): § 0.86 - 1.08 (m, 4 H), 1.94 (s, 6 H), 1.96 - 2.03 (m,1 0

H), 2.71-2.92 ) 5 H), 3.55 - 3.70 (m, 2 H), 3.86 (d, /=5.47 Hz, 2 H), 7.31 - 7.48 (m, 2

1 ml.

H), 7.69 (d, 27.42 Hz, 1 H), 7.74 - 7.84 (m, 1 H), 7.93 (t, J=8.30 Hz, 1 IT), 8.48 (d,

RX

J=4.10 Hz, 2H). MS (ESI) (M+H) = 365.04.

EA Example pyran = ybel HY = hydro (18)-1-methylethyl)-1-cyano-1( —Y] -N methylbenzenesulfonamide —N— imidazole — 0— yl] jo -151- methyl) © gi A 0 N=

CLA

© 2 - using 17-[©-amino-4-[(tetrahydro-117-pyran) 01 followed procedures eg 1.767 mmol) id 1) sulfonamide cpu methyl N= yl Methyl)amino]phenyl)-4,7-cyano-?- methylpropionic acid (VY method of preparation see step C for an example) g » 5.85 mmol Vy g » 97, mmol) » diisopropylethylamine (YT) and then in acetic acid (Jo Yr) DMF gm » 7518 mmol) in 17 1 (HATU 3 mol); MPLC ml). The crude product was purified by *0) on a layer of silica gel to obtain the title compound in the form of a solid 1 (Yor 6 g; 0.41) white in color 1

HNMR (400 MHz, CD,0D): 51.43 - 1.53 (m, 2 H), 1.54 - 1.67 (m, 2H), 1.93 (5, 6 H), \°© 238 - 2.55 (m, 1 H), 3.24 (s, 3 H), 3.32 - 3.40 (m, 2 H), 3.93 (m, 2 H), 4.44 (d, J=7.62

Hz, 2H), 7.13 (dd, J=8.79, 2.15 Hz, 1 H), 7.32 (d, J=1.56 Hz, 1 H), 7.47 - 7.57 (m, 4 H), 7.62 (d, 1=8.98 Hz, 1 H), 7.64 - 7.69 (m, 1 H). MS (ESI) (M+H) = 453.0. Anal. Calcd for C,H, )N,0,S+ 0.8 TFA+02 H,0 (547.40): C, 56.17; H, 5.38, N, 10.24; Found: © 56.05; H, 5.29; N, 10.44, Yep

1 . c£4 Jus “HY = pyran-4-ylmethyl) —HY— (tetrahydro-1-propyl-7[ -N- methyl -N-bizimidazole =0-yl]benzene sulfonamide 2 Hm .0-4-Amino-4-[(tetrahydro-117-pyran =F} 17 using 01 procedures followed example (0 al) mmol) 0.71 betzensulfonamide ( 5,7 te -17- (= yl-methyl) amino acid (1.17 mg PH) and butyric acid (VY) Method of preparation Refer to step C in an example

Hy mol)” and diisopropyl ethylamine (0.8 pH 44 mmol) in acetic acid (0 ml). It has (Jo 0) DMF mmol) in +5 YE Baham (41,7 ATU

HO/ 70660 = Yo Reversed Phase HPLC Crude product purified by 0

TFA salt JS and after freeze-drying the title compound was obtained in “CHRON (VY ch = 15) corresponding (product” HNMR (400 MHz, CD,0D): 5 1.14 (t, ] = 7.42 Hz , 3 H), 1.43 - 1.65 (m, 4 H), 1.88 - 2.04 (m, 2 H), 2.15 -235(m, 1 H), 3.16 - 3.24 (m, 2 H), 3.27 (s, 3 H), 3.31 - 3.42 (m, 2 H), 3.88 - 3.99 (m, 2 H), 4.36(d, J=7.62 Hz, 2 H), 7.31 (dd, J=8.98, 1.95 Hz, 1H), 747 - 0 7.59 (m, 5H,) 7.63 - 7.73 (m, 1 H), 7.86 (d, ]=8.98 Hz, 1 H).MS (ESI) (MH) = 428.0.

1 and .

Anal. Calcd for C,,H,;N,0,S+1.80 TFA+2.3 H,0 +0.60 CH,CN (698.88): Cz 47.78; H, 5.37; N, 7.21; Found: C, 47.76 ; H, 5.38; N, 7.20. Ex 6e “- [?-butyl-1- tetrahydro = Spy” HY == yl THY = (te b 0 imidazole -#- N= [fe methyl pe sulfonamide m » Ryl i 3 TCL 9 0 I followed the procedure of Example 01 using 17©-amino-4-[(tetrahydro-117-pyran t= -ylmethyl)amino] N= {Ue methyl benzene sulfonamide (VOT) (Bham” 171 mmol (BA) method of preparation see step h in Example 17); pentaenoic acid (1,8? TY oF mM 0 mol)” and diiso Propyl tdamine (07.8 co 88 + mmol) HATU (31.7 pg YE mmol) in DMF (0 ml) and then in acetic acid (e ml). The crude product was purified by MPLC using hexane/50/80 at a ratio of 1:1 on a bed of silica gel to yield 816.4 bahm (7074) of the title compound as a white solid. 1 HNMR (400 MHz, CD,0D): 8 1.05 (t, 17.32 Hz, 3 H), 1.45 - 1.63 (m, 6 H), 185-199 m (m, 2 H), 2.15 - 2.32 (m, 1 H,) 3.20 - 3.26 (m, 2 H), 3.27 (5, 3 H), 3.31 - 3.41 (m, 2 H),

-1 l velocity 3.85 - 4.05 (m, 2 H), 4.37 )4, 127.62 Hz, 2 H), 7.32 (dd, 18.98, 1.95 Hz, IH), 7.47 - 7.60 (m, 5H), 7.63 - 7.73 (m, 1H), 7.87 (d, J=8.79 Hz, 1H). MS (ESI) (M+H) = 442.0.

Anal. Caled for C,H,N,0,8+1.00 HCI+1.00 H,O (496.07): C, 58.11; H, 6.91; N, 8.47;

Found: C, 58.14; H, 6.92; N, 8.30. 0) eg pyran-4-ylmentheyl)-121-br —HY— (tetrahydro-1-[?-p-butyl-ethylbenzenesulfonamide —N— imidazole — 0—YL].

Dsl 8 Ne 0 Kf 0 Step A: 18 [3- + -butyl-1-(tetrahydro-87-pyran-4-ylmenhecyl) -—HY 0bizimidazole—o—yl] - 7<- ethylbenzene sulfonamide L 1 HM N IN 2] ea] Bg o M —_ 3 stirred ?- —t butyl N= ethyl -1- (tetrahydro - 117-pyran -; 01 mmol)

-141- “and sulfonamide chloride (oY) with 1.70 mmol chloride in (Jr 0) MeCN under room temperature and overnight. The reaction mixture was diluted with (01) EtOAc (J) and then washed with a saturated solution of sodium bicarbonate (01 ml) and a saturated solution of sodium chloride (01 ml)” and then dried with sodium sulfate. After evaporation, then Purify the 0 residue by MPLC and using hexane/EtOAc in a 1:1 ratio on a silica gel bed to obtain BaH (967/10) OF of the title compound as a white solid.

HNMR (400 MHz, CD, OD): 5 0.95 (t, J=7.03 Hz, 3 H), 1.36 - 1.50 (m, 4 H), 1.53 (s, 9

H), 2.08 - 2.29 (m, 1H), 3.12 - 3.27 (m, 2H), 3.65 (q, J=7.09 Hz, 2H), 3.76 - 3.88 (m, 2

H), 4.37 (d, 1=7.03 Hz, 2 H), 7.03 (d, J=8.79 Hz, 1 H), 7.32 (s, 1 H), 7.51 - 7.63 (m, 4H), 00 7.64 - 7.76 (m, 1 5 7.83 (d, 1-8.59 Hz, 1 H). MS (ESI) (M+H) - 456.0 . Anal. Calod for C,;H,,N,0,5+1.20 TFA+0.3 CH,CN (604.77): C, 55.61; H, 5.85; N, 7.64; Found: C, 55.57, H, 5.79; N, 7.61 Step N10 ethyl —f) —N — fluoro —¥ Nitrophenyl acetamide. 8 8 > x or MB N Tr a . o 8 0 Sodium hydride (0 VY g” 9070 30 mmol) was added in parts to NJ (4-fluoro-7-nitrophenyl)acetamide (3.85 g” Yo mmol) ( To know the method of preparation, see step b in example 47) in THF (001 ml) at zero degrees. And with stirring for

1627- Y min. Iodomethane (7 9.7 grams »10 mmol) was added and the reaction mixture was stirred overnight at room temperature; The mixture was then hydrated with a saturated solution of 1 sodium bicarbonate (7 mL) and extracted by 1880/6 001 * OF (mL). The combined organic phases were washed with sodium chloride (XY 71 ml). After filtration and concentration, the residue was purified by MPLC using hexane/EtOAc at a ratio of 1:1 on a bed of silica gel to yield XLT (00) of the title compound as a yellow solid. 1 H NMR (400 MHz, CDCL): § 1.14 (t,J=6.93 Hz, 3 H), 1.88 ) 3 H), 3.70 - 3.84 (q,

J=7.0 Hz, 2 H), 7.34 - 7.43 (m, 1 H), 7.48 (s, 1 H), 7.87 — 7.98 (m, 1 H). yl = f= pyran —HY— nitro -- [zetrahydro -[ —N— step C: <- ethyl 0-methyl)amino]phenyl)acetamide 1 or ~ “Or 5. a F 0 4-aminomethylpyran (1.77 g » 11.4 mmol) was added to the mixture of 17- “N= Jt (©-fluoro-3-nitrophenyl)acetamide (YLT) g (01.4 mmol)”; and 1, sodium carbonate (7.47 g” 77.9 mmol) in VO (5011 mL) at room temperature. The reaction mixture was heated for a period of lh a week under pT, and after evaporation of the ethanol, the residue was diluted with water (00 (Jo), then that substance was extracted by means of 001 XY) EtOAc

‎-167- . ml). The combined organic phases were washed with a saturated solution of NaCl (Y)Jo X and dried with sodium sulfate. After filtration and concentration, the residue was purified using MPLC and using hexane/EtOAc in a 1:1 ratio. on a bed of silica gel to obtain 7.87 grams (YoAo) of the title compound as a 0 orange-red solid H NMR (400 MHz, CDCL): 1.11 (t, J=7.13 Hz, 3 H), 1.38 - 1.52 (m, 2 H), 1.78 (m, 2

H), 1.86 (s, 3 H), 1.92 - 2.04 (m, 1 H), 3.20 - 3.29 (m, 2 H), 3.39 - 3.49 (m, 2 H), 3.71 (gq,

J=7.09 Hz, 2 H), 4.00 - 4.08 (m, 2 H), 6.91 (d, J=8.98 Hz, 1 H), 7.24 (d, /=2.54 Hz, 1 H), 8.01 (d, J =2.54 Hz, 1 H), 8.22 (t, /=4.98 Hz, 1 H). [tl pyran-4-ylmethyl) —HY— amino -- [(tetrahydro —¥} —N Step D: 0 phenyl) -<- ethyl acetamide 1 1

N to HN NH,

TCR - 7h ss 0 0 27-ethyl-17-}58-7-4-[(tetrahydro-117-pyran-4-ylmethyl)amino| {J acetamide (7.87 g” AVR mmol) in ethyl acetate FH (Je Yo 1 by Y) C/Pd 70101 0.0 g) at a pH of 31 = 40 psi in an IH Parr apparatus for 10 hours and below room temperature. After filtration through the Celit layer and after concentration, 7.45 grams (W080) of the title compound were obtained in the form of

-1662- = i_.a5 light yellow; These were used directly in the next step without additional EY ale MS (ESI) (M+H) - 292.3 - (dp) (tetrahydro-157-pyran-4-yl-1-) Step P: <- [?--butylimidazole =0— yl]-T<- ethyl acetamide.ju —H

NMH, Ig5

TL EASE

N Q N

“HY = amino-4-[(tetrahydro-©[oN) using ov followed the procedures for Step A in the example of ethyl acetamide (807.1 pH 7.75 mM); N= {Jes pyran-4-ylmethyl)amino] (Bghi YA, 4) mmol)”; and trimethyl acetyl chloride 5.50 (DMAP 117, 4) ml). The crude product was purified in (7 0 DCE then in “(J+ 1+) mmol CHCly) in = 17 on a layer of silica gel. Product (VY +) MeOH/ EtOAc and MPLC by 0

JV 154.1 BG 1

H NMR (400 MHz, Mos: § 1.12 (t, /=7.13 Hz, 3 H), 1.51 - 1.57 (m, 4 H), 1.58 (s, 9

H), 1.83 (s, 3 H), 2.21 -2.40(m, 1 H), 3.26 - 3.43 (m, 2 H), 3.78 (q, J=7.23 Hz, 2 H), 3.94 - 4.07 (m, 2H), 4.22 (d, J=7.42 Hz, 2H), 7.02 (dd, J=8.59, 1.95 Hz, 1H), 7.34 (d,

J=8.59 Hz, 1 H), 7.54 (d, J=0.98 Hz, 1 H). MS (ESI) (M+H): = 358.07. Vo

—Yéo- 0 step f ?- me butyl N= ethyl -1- (tetrahydro-17- Op -;- ylmethyl) -151- ju imidazole —0— amine . \b S CL, / — CL / dissolved -N[3?- +-butyl-1-(tetrahydro-117-pyran-4-ylmethyl)-131-Fo imidazole -#- yl] N= ethyl acetamide et THAT (7.05 mmol) in 10 ml of 3 and (2N) hydrochloric acid in a ratio of IY 7 M. Heat the mixture below 011 degrees - How long is a Personal Chemistry Smith Synthesizer microwave? hours. And after A bag and drying in medium Ae ¢ air 3 obtain Fr filled with acid Yo 1 from the title compound in the form of a grayish-white solid. 3163 - MS (ESI) (M+H) 0 Example oY -1( -7[ N= J -N methoxy -1-methyl (Jt) == (tetrahydro-117-pyran-4-ylmethyl) -151-ju Imidazole —0—yl]benzenesulfonamide © NPT D CL, JAN 0

1-p. tetrahydro-1-migylethyl)-1-megoxi-1(-7[ N= J) NG Step | Bazimidazole -*-yl]benzenesulfonamide (THY = pyran 4 - yl mephyl) —HY— ng Hy GO ade 4 a

CA _ 0 TOK 0 0 methyl -1-methoxy -1( -7- using 7<- yl (A) Follow the procedure for step A in the example of imidazole -*-amine ju mH = (Jie yl - 4- Ol -137- ethyl) == (13-hydro-0 pg” 0.177 mmol) (for the method of preparation, refer to steps b “c; 1 (5 mmol chloride)” and benzenesulfonyl chloride (45.9 mg vio. 18.0 DMAP d-phase HPLC ml). The crude product was purified by (©) MeCN; mmol) in 7 I also carried out the freeze-drying process (HO CHRON 70590 = Yo inversion) and using 1,1 district = beholder (product TFA) to obtain the title compound in the form of salt 0 (Yor 4 1

H NMR (400 MHz, CD30D): § 1.07 (t, J=7.13 Hz, 3 H), 1.48 - 1.58 (m, 4 H), 1.78 (s, 6

H), 227 - 2.51 (m, 1 H), 3.32(s, 3 H), 3.33 - 3.40 (m, 2 H), 3.72 (q, J=7.23 Hz, 2 H), 3.88 - 4.00 (m, 2H), 4.51 (d, J=7.42 Hz, 2H), 7.15 (dd, 128.88, 1.86 Hz, 1H), 7.40 (4,

J=1.76 Hz, 1H), 749 - 7.58 (m, 2 H), 7.59 - 7.64 (m, 2 H), 7.63 - 7.70 (m, 1 H), 7.76 (d, © ]=8.98 Hz, 1 H ). MS (ESI) (M+H)+ = 472.0. Anal. Calcd for C2sHssN30sS+ 0.90

1 27/- “ TFA+0.20 H20 +0.40 CH3OH (590.66): © 55.31; H, 6.13; N, 7.11; Found: C; 55.29; H, N, 7.10 | ;6.06 Step -1(-7[NJ)No hydroxy-1-methyl ichyl)-1-(tetrahydr—HY—pyran-4-yl methyl)-ju —HY imidazole-8-yl]acetamide. Bz8 ™~ NH, #< \ TL 0 10% / \ 9 The procedures for example 01 were followed using =F} =N-amino-4-[(tetrahydro-117-pyran-4-yl methyl)amine] N= ethyl acetamide (AE) g” 3.8 mmol) Bal) Method of preparation See steps b”c; D in example ))51 and ?- hydroxy (Y= methylpropionic acid (TY) gram “TAY mmol)” and diisopropyl (Jat)amine (1000+ pl 0 4.77 (1 mM HATU (7 g dpe » 7.45 mmol) in £) DMF ml then 3 acetic acid (0 ml). The product (YA)pl or elas dr > cpl was used over Yo 0 directly in the next step without further purification. .360.04 b MS (ESI) (M+H) step -1- oS ie -01( —Y] NL) Nop methyl ethyl) -1- (tetrahydro OV HY -4- yl Jo -151- (Jets imidazole —0— yl]acetamide

m ahm -1 pa m OH eH tf N > POA.

TUK sodium hydride TY,+gr» ATE 9670 mmol) was added in fractions to a solution of -N-yl-1(-7[N=oxy-1-methylethyl hydrate) -1- (tetrahydro-117-pyran-4-ylmethyl) = ju —HV imidazole [mo-yl]acetamide (0.1.7/0 g of the aforementioned 0 crude product” YAN mmol) in THF 100 ml) below zero degrees. With stirring for “0” minutes methane iodide (TRE NT FR mmol) was added and then the reaction mixture was stirred overnight at room temperature; then the mixture was hydrated with saturated glo (Jo 1) (NHLCL) It was diluted with M 8:08 001 (ml) and then washed with a saturated solution of NaCl (10 XY ml). After filtration and concentration, the residue was purified by 0 ©1001 and using MeOH EtOAc at a ratio of 1:1. 710 on a bed of silica gel to obtain “YY” grams (JOT) of the title compound in the form of a gray slay solid. MS (ESI) MH) = 374.03. Z step d:—N ethyl-?-1(methoxy-1-methylethyl)-1-(tetrahydro-—HY-pyran-4-ylmethyl)-159-ju imidazole --e- Amin M Labach HN M M #< > > ا 0 0

AR at i” - (testerhydro-1-methylethyl) -1-methoxy-1(SY]SNE ethyl SN dissolved

VAY (£YY,0) imidazole -*- yl]acetamide ju -131- pyran-4-ylmethyl) —HY Then charge the mixture (YY) 2N mL of 151011 with hydrochloric acid Vo mmol) in

Personal Chemistry Synthesizer using a 1011-type microwave device at an hour temperature. After concentrating and drying in a vacuum medium, 441.9 0% Yoo acid was obtained from the title compound in the form of a light-beige solid. (7010)

MS (ESI) (M+H) 3324

Claims (1)

Claims 1-1 Noun . A compound of formula 1 or a pharmaceutically acceptable salt thereof of I N TO ' Lo I “oy RY is selected from Crag Alkyl Caray Alkenyl Woodo© Cyclo Alkyl - Cra Alkyl; And JS Ment Alkyl © Alkyl » Ca - a large cyclic compound nis 7 Alkyl » Dicyclo Alkyl » Cay Cyclo Alkyl » Mo - Heterocyclic Compound » where the aforementioned groups are alkyl 3 Cano Alkenyl 3 Cato spcao alkyl - 6 JS mitcycloalkenyl -© SH and Cra heterocyclic 0 compound Crs alkyl, dicycloalkyl, micycloalkenyl, 6: 4 Heterocyclic compound used in the definition of ERY Optionally substitute one group or ST selectable from halogen, cyano, nitro, methoxy+, ichoxy, methyl, ethyl, hydroxy and amino. 0 and m choose th from the aS Cor JS over Sicar Co = JH alkyl mint cyclo CS alkyl “where it is in both the alkyl range” and (=I Cag Vo) and the cyclo range (SI range Cycloalkyl-. ethyl, hydroxy, and amino; Vey-. Y and Ar is chosen from Cro aryl Cay heteroaryl where in Coo YY the aforementioned aryl and heteroaryl can be optional substitution with one or more vy groups selected from Cry Alkyl Crp Alcoxi LSI Cr amine;? | Carbonyl and halogen. 1 = compound according to claim 1 where L Choose RY from Cup Alkyl cycloalkenyl Cag cycloalkyl - (JS Cra 7 cycloalkenyl - © Alkyl" is a heterocyclic group = B; (JST) where it is in each From the following masculinizing groups: Alkyl bitter Cas 0 Alkyl “JS JS fun - Alkyl bitter” Mi Cyclo SI = Alkyl bitter; Cr de po 0 3 heterocyclic - Cry Alkyl and used In the definition of RY optional substitution of y by one or more of the groups chosen com Pls a A a methoxy; 4 And the selection of T from © Alkyl “Cas Alkenel” Marah Sickler JS B Sikar 0 Alkyl - (SUT Cry Mi Cyclo Alkenel = Tower of SH) where it is in 11 immediate masculine groups : © Alkyl » Mech Alkenyl Mekler Alkyl from 1” Cyclo JST - Blending Alkyl » Mech Cyclo Alkenyl - Cr Alkyl” used in VY Definition 82 Optional substitution of one or more groups to be selected from 04 halogen, methoxy, ethoxy, hydroxy, | Alkyl; Cia » -H and the 3th of Vo is selected as a heterocyclic aryl », where it can be in Cay from vinyl Ar, and the aforementioned heteroaryl 5 is chosen by optional replacement of Cay with vinyl groups VY can be selected from Miel, Methoxy, Fluoro, and Chloro ST in one set or VA, Bromo, and Iodo. 5 © 1 : 1 - Compound By of claim No. 1 whereby a choice of cyclopentyl-methyl, cyclohexyl-methyl, 1-butyl-methyl, and cyclopropyl-methyl ety 4 - 4-methyl difluorocyclohexane” tetrahydropyranyl-methyl” tetrahydrofuranyl-methylmorpholinyl-0 methyl” and pyridinylethyl” NG methyl-piperidinyl-methyl and peridinyl methyl and 1 selection of th3 from +- butyl” ny butyl » and 7-methyl == butyl” and iso (J 1 f?- hydroxypropyl” ys methoxy “Yo propyl” and 1-methyl = = propyl” + and 1-1-dimethyl- propyl”-1-Vy-dimethyl-7-butene-1-yl-trifluoromethyl” and 1-1-difluoroethyl” and 7 7-trifluoro(REI) 0-ethyl and 7-propyl oy 11 select th1 from 11 methyl 1” and Ar is selected from phenyl,” pyridyl,” pyridyl,” lyazolyl,” linyl; 10, yis, xazolyl,” imidazolyl,” and pyrazolyl,” which can be in 0 groups The aforementioned vinyl, piperidyl, percadinyl, thiazolyl, chenyl, lyase, xazolyl 10, imidazolyl, and pyrazolyl are optional substitutions of one group or more. selected from Jit and Mythoxy; and fluorine and chloro. 1 4 - Compound By of claim No. 1 where “RY is selected from cyclohexyl-methyl” and methyl tetrahydropyranyl and 4,4-di-0fluorocyclohexanemethyl; ARTE +-butyl” and 111-difluoroethyl; 0 is selected from cH and methyl; and are selected from phenyl, pyridyl, thiazolyl, thienyl, yase, xazolyl, VY, imidazolyl, and piperazolyl, where an optional substitution can exist in Sle pat A phenyl, pyridyl, thiazolyl, thinyl, and yase And xazolil, imidazolil, and pyrazolil Core. 4 with one or more methyl groups. 1:© - compound selected from: NY [7-p-butyl-1-(cyclohexylmethyl) = ju HY imidazole —o= [LY thiophene-7-sulfone amide mY]Ng butyl-1-(cyclohexylmethyl)-111- jo imidazole mo N= [he methylthiophene-3?-sulfoneamide; (hp -V)-N 0 - ?- + -butyl-111-ju imidazole -*#-yl) N= decyl 1-butylsulfoneamide; NA [”-:-butyl-1-(cyclohexylmethyl)-111-jo imidazole =o 9yl] =o 7 N= trimethylis and xazole-4-sulfone amide Ny[?-p-butyl-1-(cyclohexylmethyl)-111-bizimidazole mo 01 N= [VY 7-trimethyl-131-imidazole-4-sulfonamide; 7<[?-mt butyl N=(cyclohexylmethyl)-111-ju imidazole mom 07yl] 1N-7 0~tetramethyl-111-pyrazole-4-sulfone amide 14<-[?-mt butyl-1-(cyclohexylmethyl)-111-ju imidazole -0-cape[ve sulfoneamide; -1[ < 7 5 |(cyclohexylmethyl)-7-ethyl-151-jo imidazole-h-yl] VY-betsulfonamide; -1[ < 7 8 (cyclohexylmethyl) - ?- isopropyl = ju HY imidazole —o = 8 yl] benzulfonamide; -1[NY (cyclohexylmethyl) -7- -1(methylcyclopropyl) -111-btr 1imidazole m=yl]betsulfonamide; -1[ < 7 vy (cyclohexylmethyl) - 7- 1 » 1(dimethylpropyl) -111-pyr YY imidazole -#-yl]betsulfonamide; ete. -1[oN vy (cyclhexylmethyl) -1 a)mvs dimethyl THY (J petr vy imidazole =o= yl]benzene sulfamide; -1[ -<7 (cyclohexylmethyl)-7-Ji)-131-butyrimidazole [de ~o= = -N YQ methylbutynsulfonamide; -1[-<#0 (cyclohexylmethyl) Y = isopropyl = je HY imidazole Tom 1 yl]methylpo sulfoneamide; -1[ < 7 vy (cyclohexylmethyl) -7- -1 (methylcyclopropyl) THY petr vr imidazole —o= yl] N= methyl-benzenesulfonamide; VV) 7[ 7 vt dimethylethyl)-1-[xtrahydro-1577-pyran-4-yl)vomethyl]-131-butyrimidazole=oyl]-benzenesulfonamide; 7 7<[7 1017-dimethyl)-1-[tetrahydro-7-furanyl)methyl] = “HY”© bizimidazole-73-yl]-btzensulfonamide;-1[< 7 + (cyclobutylmethyl) -7-,-1”(dimethylethyl)-111-btr4imidazole -#-yl]benzenesulfonamide; -1[oN 0 (cyclopropylmethyl) -1 Oy Y = dimethyl)-111-br 1imidazole -#-yl]benzene sulfamide;oN gy [*- +-butyl-1-)8hydro-117-pyran-4 -ylmethyl) = Fe THN + imidazole —o= yl] =N= methylbenzenesulfonamide;4|7<-[7-+butyl-1-(tetrahydr-147-pyran) - ?- ylmethyl) -111- petr to imidazole -#- yl]-38-methylbenzenesulfonamide;-1[oN 4(cyclohexylmethyl)-7--1(hydroxy- 1-methylethyl)-NO HY imidazole -*-yl]betzenesulfonamide; -1[aN gA (cyclohexylmethyl) -1(SY mechoxy -1-methyl TE . e jo —HY £9 imidazole -*- yl] N = methyl = betzensulfonamide; -1[37 0 (cyclohexylmethyl) -7- 1-(methoxy -1-methyl) (El - ju -131 51 imidazole =oyl] = betzensulfonamide; 0” 7<-[7-?-butyl-1-(cyclohexylmethyl)-111-ju imidazole—o=-1 N= [eo dy” HV = Jin imidazole-4-sulfoneamide; ee 7<(e-eX]butyl-1-(cyclohexylmethyl) = THY petyrimidazole -#-yl[(methyl)amino]sulfonyl)-4 -methyl = oT yazole = 4 0 ?- yl)acetamide; Lah 7 < [?-:-butyl-1-(cyclohexylmethyl)-111-ju imidazole -0-0A yl] N=methylpyridine-7-sulfoneamide; t=]N08-butyl-1-(cyclohexylmethyl)-131-benimidazole=m 0yl]1 N= ? -trimethyl-131-imidazole -*-sulfoneamine;+1 7<[?-:-butyl-1-(tetrahydro-117-pyran-4ylmethyl)-111- Ft TY imidazole -*#-yl] 0 N= ?-trimethyl-131-imidazole—o= sulfone MY amide;=Y 00 27% trimethyl = HV imidazole —0—sulfone amide; gal ve -4- ([[7- »-butyl-1-(tetrahydro-133-pyran-4-yl Stor 1121-3-butylimidazole -#-yl] (methyl) amino]sulfonyl) =o r= die methyl] TY -111-pyrrole =V= carboxylates; A 7<-[7-:-butyl-1-(tetrahydro-?11-pyran-4ylmethyl)-111-bt-4imidazole [=o-4-(hydroxymethyl) N= METHYL BETZINE SULFONAMIDE; Nv. [7-:-butyl-1-(tetrahydro-117-pyran-4-ylmethyl) = THY petr-1 imidazole -#-yl] -8<- =r oY oF -131(-4-Jie triazole -1-lyl VY methi)benzene sulfamide; -N VY [7-? -butyl-1-(tetrahydro-117-pyran-4-ylmethyl)-111-butyr yon : Jeter N= imidazole-H-yl]-4-([(-hydroxyethyl)amino]methyl)VE Vo benzenesulfamide; 27 [?- + butyl-1-(cyclopentylmethyl) = HV bisimidazole —o= yl] N= YY methylbenzenesulfonamide; SN YA [”-:-butyl-1-(cyclohexylmethyl) = mH b-imidazole -e- VA yl]-128-methylbetzine sulfamide; -1( -1 -N - 0-benzyylpyrrolidine - ?-yl) -?- + -butylju -110-imidazole | Methylbetzinesulfoneamide; N= yl] -#- AY - [der (Jeo difluorocyclo-4 4)([ -1- butyl mt ?- 1 -< AY AY 111b imidazole -#-yl)-27-methylbenzenesulfonamide; —o= imidazole ju -111-(pyridine-4-ylmethyl)-1-butyl -t=] NAS Ao yl] N= methylbenzene sulfamide; -N AR methyl-7<--1[(tetrahydro-117-pyran-4-ylphenyl)-7-(tri (L-Fluoromethyl)-111-PTZimidazole -#-yl]btzensulfonamide; NAA [7-(1a)=difluoroethyl)-1-(tetrahydro-187-pyran-4-yl (AS methyl)-131-petzimidazole [mo yl] “N= methyl pfu sulfamide; -N” 0methyl [-1] N= (tetrahydro-1177-pyran - ;- yl yl =Y= td 1 ?-trifluoroethyl) = HY ptzimidazole -#-yl]btzensulfonamide; -1[ < 7 7 (cyclohexylmethyl) -7- -1-(ethylpropyl) -151-biz imidazole ‎ay -#- yl]methylbenzene sulfamide; z 4 7<[?- +-butyl-1-(cyclohexylmethyl)-111-ju imidazole—o— 8 yl] N= ethyl benzene sulfamide; Namethyl-1( SY] NS methyl-1-pyridine-7-yl-1- (td (tetra) 7 hydro-117-pyran mE yl methyl) jo SHV imidazole mom yl it 4A Sulfonamide; Mlg|1|0:48 to-[7-,-1(cyano-1-methyl-1-(Jel) (tetrahydro-117-pyran--0-ylmethyl) = ju —HV imidazole -*# -yl] N=methylbetzinesulfoneamide; 011<7methyl” N=[7-propyl-1-(tetrahydro-117-pyran-4) (-ylmethyl)-0" 111-bizimidazole [=o-yl]btzenesulfonamide; 0" 37]= butyl-1-(tetrahydro-?13-pyran-4-ylmethyl) -111- petr04 imidazole -#-yl] -N=methylbenzene sulfoneamide;-N0[?--butyl-1-(tetrahydro-13-7-pyran-4) - yl “HV = (Jeter V1 0 imidazole ==[-28-ethylbenzenesulfonamide; ºN 0” ethyl-27-[7--1(mechoxy-1-methyl) ethyl)-1-(tetrahydro-—HY 0 pyran-4-ylmethyl)-171-ju imidazole =0—yl] pio sulfoneamide;9"\ and its pharmaceutically acceptable salts. M compounded pursuant to any of the claims of \J 0 for use as a drug. = Use of a compound pursuant to any of the claims 1 through 0 in the manufacture of drug Y for the treatment of A 4 -A \ use M compounded pursuant to any of PROTECTIONS FROM \ TO 0 3 MANUFACTURE OF MY MEDICINE Anxiety Disorders 1 +- Compound use according to any of Claims 1 to 0 in the manufacture of Drug Y for the treatment of cancer ¢, multiple sclerosis, Bar-Kelson's disease, Huntington's chorea[4], Alzheimer's disease, and (aa) digestive disorders; and cardiovascular disorders. iy A \ pharmaceutical composition comprising a compound according to any of the Claims of 1 M SMH -1 0 - 1 7 L * and a pharmaceutically acceptable carrier. y \ 1 - A method of preparing a compound of formula I | 1 : oR WN N _ Y - no Ar 0 Cr 1 6 4 R I includes a complex reaction step of formula [1 a a] and nosem ° 0 rR I ‏ . With a compound of formula COX 2l in the presence of its base Jes the alkylamine and optionally 3<7 in the presence of a coupling substance “EDC HAT Jo” and where A is chosen X from ¢OH Fy Bry CI q is RY selection from Ciao alkyl Ca108 alkyl xodo cyclo-alkyl — (Si Cia i HS Cas) \ Laknia “JS Cia Min - heterocyclic compound — Cig 0 alkyl 0, 0 cycl Cis (JS cyclo JS Mo - noncyclic compound (lone \ Y) in which the said groups are 0-01 “JS and 0-02 alkenyl; Cs. 4s 'yr | 10 cycloalkyl — Cass “JS Cia cyclo Cia — JER Alkyl. Cis 0 heterocyclic compound 04 (JS and 0 d cyclo-alkyl. 9 Cas cyclo-alkyl” or Cag heterocyclic compound ; used in defining T Ls \o 0 optional substitution of one or more groups to be selected from halogen, cyano-nitro, mech-roxy oS sly, methyl, ethyl, hydroxy and amino; VA and R? to be chosen from and 6 JS Moon Alcanel 00 Cyclo “JS Medo SS yoda 1 per - Met JS Hat Cyclo Al-Kanil - M6 Al-Kail “where it is in each of the 7 cities of Al-Kail” or Madih Al-Kail “or Mado Cyclo Al-Kail” or Coo Cyclo Al-Kail - YY M6 (JST or micycloalkenyl = (JS Crp) used in defining R? Optionally substituted with one or more groups to be chosen from the mamalogens “YYa” and the methoxy; BE is chosen from Cr ly alkyl metalkyl Jet AS Erg YT from cyclic alkyl - from CUS YY and Ar is selected from m© aryl Cay heterocyclic aryl where it can In the aforementioned heterocyclic YA called Jil Cosy Jif optional substitution of one or more groups 1 4 is selected from an alkyl bitter alkyl and x; Cr alkyl amino© carbonyl and halogen.